Enol Phosphates Research Articles

Versatile dehydrogenation of carbonyls enabled by an iodine(III) reagent.

We report the utilisation of an iodine(III) reagent to access α,β-unsaturated carbonyls from the corresponding silyl enol ethers of ketones and aldehydes, and from enol phosphates of lactones and lactams. The transformation is rapid, scalable, and can be carried out in one pot, directly dehydrogenating saturated carbonyls.

Enol phosphates from 3-diethylphosphonocoumarin: synthesis and transformations under phase-transfer conditions

Enol phosphates were prepared from 3-diethylphosphonocoumarin under phase-transfer conditions as altered conditions for tandem hydrogenation / phosphorylation reactions. The optimized reaction conditions are characterized with high regioselectivity for O-phosphorylation and O-acylation. The newly synthesized enol phosphates were fully characterized by NMR Spectroscopic techniques and the single (Z)-isomers were assigned.

Stereoselective synthesis of (E)-α,β-unsaturated esters: triethylamine-catalyzed allylic rearrangement of enol phosphates.

α,β-Unsaturated esters are key structural motifs widely distributed in various biologically active molecules, and their Z/E-stereoselective synthesis has always been considered highly attractive in organic synthesis. Herein, we present a >99% (E)-stereoselective one-pot synthetic approach towards β-phosphoroxylated α,β-unsaturated esters via a mild trimethylamine-catalyzed 1,3-hydrogen migration of the corresponding unconjugated intermediates derived from the solvent-free Perkow reaction between low-cost 4-chloroacetoacetates and phosphites. Versatile β,β-disubstituted (E)-α,β-unsaturated esters were thus afforded with full (E)-stereoretentivity by cleavage of the phosphoenol linkage via Negishi cross-coupling. Moreover, a stereoretentive (E)-rich mixture of a α,β-unsaturated ester derived from 2-chloroacetoacetate was obtained and both isomers were easily afforded in one operation.

Preparation of an advanced intermediate for the synthesis of leustroducsins and phoslactomycins by heterocycloaddition.

A convergent strategy for the synthesis of leustroducsins and phoslactomycins has been designed, relying on the synthesis and the coupling of three main fragments. The central fragment was synthesized via a regio-and stereoselective nitroso Diels–Alder reaction with an enol phosphate, followed by reductive cleavage of the phosphate to the ketone 11b. Coupling studies of this fragment with the lactone fragment was accomplished in a stereoselective fashion through a vinyllithium intermediate. An advanced synthetic intermediate was then obtained after functional group transformation.

Utility of 2-Diphenylphosphoryloxy-1,3-Dienes in Multicomponent Hetero-Diels-Alder Reactions to Construct Functionalized Six-Membered Nitrogen Heterocycles.

The utility of 2-diphenylphosphoryloxy-1,3-dienes for the construction of substituted six-membered nitrogen heterocycles is presented. These dienes undergo boron trifluoride-promoted aza-Diels-Alder reactions when reacted with imines or related species formed in situ using aldehydes and amine derivatives. The stability of the dienes allows this three-component reaction to be carried out with no special precautions to eliminate water or air. Thirty-one examples of this process are presented. The usefulness of the enol phosphate functional group is highlighted in further reactions after the cycloaddition step to generate functionalized piperidenes or pyridines.

Regio- and Stereoselective Synthesis of Enol Carboxylate, Phosphate, and Sulfonate Esters via Iodo(III)functionalization of Alkynes.

β-Iodo(III)enol carboxylates, phosphates, and tosylates can be efficiently synthesized through regio- and stereoselective iodo(III)functionalization of alkynes. The combination of chlorobenziodoxole and silver salt has proven to generate a versatile cationic iodine(III) electrophile to activate alkynes and engage various carboxylic acids, triethyl phosphate, and p-toluenesulfonic acid as nucleophiles. The β-iodo(III)enol esters serve as starting materials for the synthesis of multisubstituted alkenes through sequential cross-coupling of the C-I(III) and C-O bonds.

Nickel-Catalyzed Kumada Vinylation of Enol Phosphates: A Comparative Mechanistic Study

Based on supporting stoichiometric organometallic syntheses, structural analyses, reaction monitoring, radical-clock experiments, and kinetic investigations, a comparative mechanistic study between two related systems that are competent in the Ni-catalyzed Kumada cross-coupling reaction between enol phosphates and vinyl magnesium bromide is reported. We demonstrate that the two bisphosphine–nickel complexes operate via Ni(0)/Ni(II) catalytic manifolds for this type of C(sp2)–O electrophiles. The first complex of generic structure [(dppe)NiBr2] is reduced in situ upstream from the productive catalytic cycle, which itself follows a classical mechanistic scenario composed of an oxidative addition/transmetalation/reductive elimination sequence. A rapid phosphate/bromide ion exchange prior to transmetalation constitutes a key feature of this system. The related [(dmpe)NiBr2] complex follows a much less conventional pathway. Kinetic analyses distinguish themselves by an unusual apparent second order in the catalyst, which is attributed to an interplay between vinyl nickel species formed during precatalyst activation and styrenyl nickel intermediates generated downstream in the sequence of elementary steps. This hypothesis is corroborated by independent supporting organometallic investigations.

Synthesis of Silylated Cyclobutanone and Cyclobutene Derivatives Involving 1,4-Addition of Zinc-Based Silicon Nucleophiles.

A copper‐catalyzed conjugate silylation of various cyclobutenone derivatives with Me2PhSiZnCl ⋅ 2LiCl or (Me2PhSi)2Zn ⋅ xLiCl (x≤4) to generate β‐silylated cyclobutanones is reported. Trapping the intermediate enolate with ClP(O)(OPh)2 affords silylated enol phosphates that can be further engaged in Kumada cross‐coupling reactions to yield silylated cyclobutene derivatives.

Access to Highly Stereodefined 1,4-cis-Polydienes by a [Ni/Mg] Orthogonal Tandem Catalytic Polymerization.

A [Ni/Mg]-catalyzed orthogonal tandem polymerization has been developed starting from enol phosphates. Initial investigations conducted on branched 1,3-dienes as monomers enabled identification of a Mg-initiated polymerization process leading to 1,4-cis-polydienes. When aryl enol phosphates are used as monomers, the [Ni/Mg]-catalyzed tandem polymerization affords 1,4-cis-polydienes with selectivities up to 99%. Elastomeric or crystalline materials were obtained by simple structural modifications of the monomeric unit. This tandem approach appears as a straightforward and efficient way to enforce diversity and selectivity in diene polymerization while retaining a fair degree of control, just as observed for stepwise systems that are accessible through established time- and manpower-consuming synthetic procedures.

Electrochemically driven desaturation of carbonyl compounds.

Electrochemical techniques have long been heralded for their innate sustainability as efficient methods to achieve redox reactions. Carbonyl desaturation, as a fundamental organic oxidation, is an oft-employed transformation to unlock adjacent reactivity through the formal removal of two hydrogen atoms. To date, the most reliable methods to achieve this seemingly trivial reaction rely on transition metals (Pd or Cu) or stoichiometric reagents based on I, Br, Se or S. Here we report an operationally simple pathway to access such structures from enol silanes and phosphates using electrons as the primary reagent. This electrochemically driven desaturation exhibits a broad scope across an array of carbonyl derivatives, is easily scalable (1-100 g) and can be predictably implemented into synthetic pathways using experimentally or computationally derived NMR shifts. Systematic comparisons to state-of-the-art techniques reveal that this method can uniquely desaturate a wide array of carbonyl groups. Mechanistic interrogation suggests a radical-based reaction pathway.

Synthesis and Structural Implication of the JKLMN-Ring Fragment of Caribbean Ciguatoxin C-CTX-1

Synthesis of the JKLMN-ring fragment of Caribbean ciguatoxin C-CTX-1, the causative toxin of ciguatera fish poisoning in the Caribbean Sea and the Northeast Atlantic areas, is described in detail. Key to the synthesis are a [2,3]-sigmatropic rearrangement to construct a seven-membered α-hydroxy exo-enol ether, stereoselective construction of an angular tetrasubstituted stereogenic center on the seven-membered M-ring by a hydrogen atom transfer-based reductive olefin coupling, Suzuki-Miyaura coupling of the KLMN-ring enol phosphate with a highly congested M-ring, and silica gel-mediated epoxide ring opening to form the J-ring. Comparison of the nuclear magnetic resonance spectroscopic data for the synthesized fragment with those for the natural product provided support for the formerly assigned structure of the N-ring in the right-hand terminal of C-CTX-1.

Synthesis and structure determination of diastereomeric carbapenems in the AdNE-reaction of (±)-4,4-dimethyl-3-mercaptodihydrofuran-2(3H)-one with chiral carbapenem enol phosphate

Synthesis and structure determination of diastereomeric carbapenems in the AdNE-reaction of (±)-4,4-dimethyl-3-mercaptodihydrofuran-2(3H)-one with chiral carbapenem enol phosphate

Nonclassical Abramov Products Formed on Orifices of Cage-Opened C60 Derivatives.

By nucleophilic addition of phosphite P(OMe)3 to a cage-opened C60 derivative, α-hydrophosphate and enol phosphate were obtained as kinetic and thermodynamic products, respectively. Different from classical Abramov products bearing a phosphorus-carbon bond, these products have a phosphorus-oxygen bond. The observed anomaly originates from the fully conjugated π system, which significantly stabilizes zwitterionic intermediates bearing a phosphorus-oxygen bond. The thus formed enol phosphate was found to exhibit an intense absorption band that extended to 730 nm, reflecting the intramolecular charge-transfer transitions. We also report domino phosphorylation reactions, which gave a cage-opened C60 derivative bearing a direct P-C bond.

Metal‐Free Hydrophosphoryloxylation of Ynamides: Rapid Access to Enol Phosphates

AbstractWe herein report a metal‐free hydrophosphoryloxylation of ynamides with phosphoric acids, which provides an expeditious route to access useful enol phosphates. The advantages of this protocol include exclusive selectivity, short reaction time, high efficiency, and broad substrate scope. Additionally, the products can serve as good partners in Suzuki‐Miyaura cross‐coupling.

Regioselective O/C phosphorylation of α-chloroketones: a general method for the synthesis of enol phosphates and β-ketophosphonates via Perkow/Arbuzov reaction.

A regioselective O/C phosphorylation of α-chloroketones with trialkyl phosphites was performed for the first time, which employed solvent-free Perkow reaction and NaI-assisted Arbuzov reaction under mild conditions respectively. Versatile enol phosphates were prepared in good to excellent yields as well as β-ketophosphinates.

LiI/TBHP Mediated Oxidative Cross‐Coupling of P(O)–H Compounds with Phenols and Various Nucleophiles: Direct Access to the Synthesis of Organophosphates

An efficient and mild method for the direct phosphorylation of phenols, alcohols, and amines with P(O)–H has been reported by LiI/TBHP mediated oxidative cross‐coupling reaction. Moreover, this protocol extended to β‐keto esters for the synthesis of enol phosphates using H‐phosphonates. Notably, this developed method applied for the synthesis of organopesticides such as paraoxon, cyanophos, and methyl parathion. The key features of this protocol are mild conditions, short reaction time, good functional group tolerance, and broad substrate scope.

Synthesis and In Vitro Antibacterial Activity of New C-3-Modified Carbapenems

New C-3 modified carbapenems have been synthesized by the AdNE-substitution of the enol phosphate group of 4-nitrobenzyl (4R)-3-[(diphenylphosphoryl)oxy]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-en-2-carboxylate by the corresponding thiols in acetonitrile in the presence of diisopropylethylamine (DIPEA). Mercaptoacetic acid methyl ester, furan-1-methylthiol, methyl N-(mercaptoacetyl)methioninate, and 2-(4-methylpiperazin-1-yl)-2-oxoethanethiol as thiols have been used. As a result, we have obtained the expected 4-nitrobenzyl esters of 3-[(2-methoxy-2-oxoethyl)thio]-, 3-[(2-furylmethyl)thio], 3-{[2-(4-methylpiperazin-1-yl)-2-oxoethyl]thio}, and 3-[((2-(S)-1-methoxy-4-methylthio-1-oxopropan-2-yl)amino)-2-oxoethyl]thio derivatives of (4R,5S,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid in yields of 67–87% after purification by column chromatography. The p-nitrobenzyl (pNb) esters of carbapenems have been converted to the corresponding acids by hydrogenolysis over 10% Pd/C in methanol. The antibacterial activity of the resulting carbapenems and their preceding pNb-esters has been studied against microorganisms of Escherichia coli, Pseudomonas aeruginosa, Candida albicans, and Streptococcus oralis. The compounds that have been found exceed in their activity the known drugs Meropenem and Cilapenem.

Three-step synthesis of chiral and sterically hindered amino alcohols based on cyclic enol phosphates

The new synthesis of chiral and sterically hindered 1,2-amino alcohols derivatives of 2-methyl-indane and 1,2,3,4-tethrahydrophenanthrene based on cyclic enol phosphates were investigated. The desired products were obtained using three step procedure: oxidation of accessible enol phosphates, transformation α-hydroxy ketones into corresponding oximes and finally reduction of the last one to 1,2-amino alcohols. The optimal conditions of all stages to obtain products with high enantioselectivity or diastereomeric ratio were found and elaborated. The structures and absolute configurations of (3R)-2,3-dihydro-3-hydroxy-1H-phenanthren-4-one and corresponding oxime were confirmed by X-ray analysis.

Regioselective addition of phosphites to acyl cyclopropanes and following rearrangements: a facile access to enol phosphates.

An inorganic base-promoted domino reaction with organophosphites and acyl cyclopropane derivatives is developed and proved to provide an efficient access to functionalized enol phosphates. Unlike the well-known Perkow reaction, which employs trialkyl phosphite as the nucleophile, dialkyl phosphite is the key to the success of our transformation. This method is compatible with a series of dialkyl phosphites and acyl cyclopropanes possessing electron-withdrawing substituents, and an array of functionalized enol phosphates are successfully prepared. Based on the results of isotope-labeling and control experiments, this transformation is presumably initiated by the deprotonation of dialkyl phosphite and the following nucleophilic addition/anion shift/ring opening sequence leads to the formation of enol phosphates. Both the strain release of a three-membered ring and the formation of a relatively stable anion are indispensable driving forces for this process.

Short synthesis of racemic 5-hydroxy-6-hydroxymethylpiperidin-2-one

Abstract A short synthetic sequence to rac-5‑hydroxy‑6-hydroxymethylpiperidin-2-one, a useful intermediate in the synthesis of polyhydroxylated piperidine alkaloids, was based on the hydroboration/oxidation reaction of a 6-furanyl-1,2,3,4-tetrahydropyridine derivative prepared from δ-valerolactam by a Suzuki–Miyaura reaction of the corresponding enol phosphate. Two subsequent RuO2-catalyzed oxidation steps concluded the synthesis. By this approach, the title lactam was readily obtained in a suitably protected form on the nitrogen and oxygen atoms for its further elaboration. All new compounds were fully characterized by NMR spectroscopy and mass spectrometry.