Horner-Wadsworth-Emmons Research Articles

Radical Alliances: Solutions and Opportunities for Organic Synthesis

AbstractThe present account discusses in detail various mechanistic features of the degenerative radical addition‐transfer of xanthates and related thiocarbonylthio congeners and makes a comparison with the more classical Kharasch reactions to which it is similar in certain aspects. The xanthate group reacts reversibly with the ‘active’ radicals in the medium and is able to store them in a somewhat inactive form. This increases their effective lifetime in the medium and, at the same time, lowers their absolute concentration while regulating their relative concentration. These properties translate into a powerful carbon–carbon bond forming process, especially as regards intermolecular additions to electronically unbiased (‘unactivated’) alkenes. Most functional groups are tolerated, in particular polar functions that often require protection with other chemistries. This broad versatility is illustrated by examples where the xanthate addition to the alkene is combined with other, more classical reactions to provide a convergent, rapid access to a wide range of useful structures. Emphasis has been placed on the synthesis of open chain and more complex carbocycles, as well as on the transfer of chirality. These ‘radical alliances’ include organosilicon chemistry, the Diels–Alder cycloaddition and cheletropic extrusion of sulfur dioxide, the Claisen sigmatropic rearrangement, and the Horner–Wadsworth–Emmons (HWE) condensation.

A Concise Total Synthesis of (±)-Camptothecin

A total synthesis of racemic camptothecin, characterized by a concise construction of the ring systems and easy functional group transformation, is described. A domino reaction consisting of a Heck reaction and an aza-intramolecular Michael addition to form the C ring serves as the first key step in the synthesis. The D ring was constructed by a simple Wittig–Horner reaction followed by removal of the protective groups. Hydroxymethylation, demethylation, and lactone formation reactions were performed in one-pot to construct the E ring under hydrobromic acid conditions. This work provides an efficient scheme for further synthetic exploration of camptothecin and its analogues.

Total Synthesis of Luminmycin A, a Cryptic Natural Product from Photorhabdus Luminescens

Luminmycin A, a natural proteasome inhibitor transcripted by a silent gene cluster from Photorhabdus luminescens, belongs to the compound family of the syrbactins and is structurally closely related to the glidobactins. Key step for the synthesis of the 12‐membered cyclopeptide ring is an intramolecular Horner–Wadsworth–Emmons reaction, while the double unsaturated fatty acid side chain can be obtained via phosphane‐catalyzed isomerization of a corresponding acetylenic fatty acid ester.

The First Total Synthesis of (±)-Methyl Salvianolate A Using a Convergent Strategy.

Herein, a convergent, practicable and first total synthesis of the natural product, (±)-methyl salvianolate A, is reported. The key features of the approach are the use of a Horner–Wadsworth–Emmons reaction and the protection of multiple hydroxyls using silyl protecting groups. The employment of the readily removable silyl protecting groups allows the synthesis of (±)-methyl salvianolate A and its derivatives on a reasonably large scale.

Application of liposome membrane as the reaction field: A case study using the Horner–Wadsworth–Emmons reaction

The properties of the liposome membrane as a reaction field were investigated by focusing on the Horner-Wadsworth-Emmons reaction as a case study. Use of the liposomes existing in the gel phase resulted in the enhanced activity of the substrates and furnished the products with same E/Z stereoselectivity as in the liposome-free system. The membrane environment in the gel phase most likely assisted the formation of adducts that induced selective generation of the E-isomer. The possible role of liposomes is to assist the proton removal from the reactant, rather than providing the basic interfacial environment.

Synthesis of the C1–C17 Segment of Bafilomycin N

The C1–C17 segment of bafilomycin N has been synthesized. The C1–C11 segment was synthesized by the anti-selective vinylogous Mukaiyama aldol reaction with a chiral vinylketene silyl N,O-acetal and the Horner–Wadsworth–Emmons reaction, whereas C12–C17 was constructed by the syn-selective vinylogous Mukaiyama aldol reaction and the Jung’s semipinacol rearrangement. Those segments were connected by the Stille coupling to afford the C1–C17 segment.

Hydrophosphonylation of chiral hexahydroquinoxalin-2(1H)-one derivatives as an effective route to new bicyclic compounds: Aminophosphonates, enamines and imines

A series of new aminophosphonate and phosphonic acid derivatives of hexahydroquinoxalin-2(1H)-ones and tetrahydroquinoxalin-2(1H)-ones were synthesised via hydrophosphonylation of the corresponding bicyclic imines with various dialkyl or diaryl H-phosphonates, H-phosphinates or H-phosphine oxides as phosphorus nucleophiles. The utility of the obtained compounds was demonstrated by their application as a source of phosphonate carbanion in the Horner-Wadsworth-Emmons (HWE) reaction leading to new bicyclic amines with an exocyclic, and unexpectedly, also endocyclic double bond depending on the structure of the aldehyde used.

Scalable Preparation of Methylated Ando-Type Horner–Wadsworth–Emmons Reagent

The Horner–Wadsworth–Emmons (HWE) reactions are vital to the chemical synthesis of complex molecules, forging a carbon–carbon double bond in the generation of α,β-unsaturated enoates from aldehydes or ketones. Despite their frequent use, the Z-stereoselective formation of α,β-unsaturated esters from aldehydes have been mostly limited to the use of the commercially available Still–Gennari reagent. Ando developed an alternative reagent to achieve the same formation with less expensive reagents. However, an α-methylated Ando-HWE reagent has remained difficult to prepare, hindering a reliable route to α,β-disubstituted Z-enoates. Here, we report the development of a preparative synthesis of a methylated Ando-HWE reagent for the highly Z-selective HWE reaction. Costing $0.49/mmol, this synthesis is significantly cheaper than the currently available Still–Gennari reagent ($11/mmol, Millipore Sigma 2018). The purification procedure does not require chromatography, with recrystallization as the only purification ...

Synthesis of novel oil-soluble fluorinated surfactants via Wittig-Horner reaction

In this paper, the synthesis and characterization of novel oil-soluble fluorinated surfactants were reported. Both Wittig and Wittig-Horner reaction were used for constructing the perfluorinated branch-chain structure, and the latter provided a better method through a three-step synthesis route which was easy worked up and low cost. The surface tension of novel products in toluene, n-hexane and nitromethane with concentrations of 0.1 mol/L, 0.05 mol/L, 0.025 mol/L, 0.0125 mol/L, 0.00625 mol/L and 0 mol/L were examined. The surface tension research of these surfactants showed that they can reduce the surface tension of organic reagents dramatically. For example, compound 1e can reduce the surface tension of nitromethane from 36.6 mN/m to 24.2 mN/m in the concentration of 0.1 mol/L, and the surface tension of toluene was reduced from 28.0 mN/m to 22.7 mN/m when the concentration of compound 1a was 0.1 mol/L.

Di-styrylanthracenes as established AIEgens: Can Di-anthracylethenes be AIE-active?

Di-styrylanthracyl (DSA) derivatives are well established AIEgens in the literature with potential applications. However, molecules with anthracyl rotors in an ethenyl stator are sporadically examined as AIEgens. In this context, sterically crowded symmetrically and unsymmetrically substituted (E)-bis-9-anthracenylethenes or di-anthracylethenes are synthesized preferably via oxidative dephosphorylation of the corresponding phosphonates or by simple but effective Horner-Wadsworth-Emmons (HWE) reactions. The use of transition metal/ligand combination is completely avoided to create such molecules. The AIE-studies of these molecules in acetonitrile/water medium exhibited the positive result. In particular, unsymmetrically substituted analogs are relatively more AIE-active. The crystal structures and molecular packings for few molecules are examined to explain the photophysical behavior both in molecular and aggregate state. The crystallographic studies specify the conformational flexibility for these molecules. The AIE-behaviors are also supported by dynamic light-scattering and time-resolved fluorescence studies.

Total synthesis, stereochemical assignment, and biological evaluation of L-755,807

The relative and absolute configurations of L-755,807 were established through total synthesis. All four possible stereoisomers were prepared via a convergent synthetic strategy, including a novel diastereoselective Darzens reaction of an α-alkoxy aldehyde with di-tert-butyl bromomalonate, an E-selective Horner–Wadsworth–Emmons reaction, and late-stage coupling of the ring and side-chain segments. Additionally, biological evaluation of the synthesized compounds revealed their potent inhibitory activities (IC50 = 5–21 μM) against amyloid-β aggregation for the treatment of Alzheimer's disease.

Synthesis and in vivo anti- or pro-inflammatory activity of new bisphosphonates and vinylphosphonates

We herein report the synthesis and in vivo anti-inflammatory activity of a series of new bisphosphonate and vinylphosphonate derivatives of pyrrolidine and piperidine through a short route of synthesis. The C-alkylation of tetraethylmethylene diphosphonate with N-(bromoacetyl)pyrrolidine or N-(bromoacetyl)piperidine, respectively, yielded the corresponding α-substituted bisphosphonates in excellent yields (82–89%). Next, the Horner–Wadsworth–Emmons reaction of these bisphosphonates with aromatic aldehydes afforded final vinylphosphonates in moderate yields (26–36%). Synthesized bisphosphonates and vinylphosphonates were tested by two models of acute inflammation in male BalB/c mice, founding excellent edema inhibition by topical TPA (12-O-tetradecanoylphorbol-13-acetate) model (67.53–72.10% in comparison with indomethacin = 64.89%). However, remarkably pro-inflammatory effect by systematic carrageenan model (− 9.78 to − 36.18) was observed, probably due to biotransformation. In conclusion, the new vinylphosphonates emerged as attractive topical anti-inflammatory compounds that “twist” its pharmacological activity to route of administration. Further research is needed to understand the dual effect.

Stereoselective Total Synthesis of Macrolide Sch-725674 and C-7-epi-Sch-725674

The stereoselective total synthesis of Sch-725674 in 14 ­linear synthetic steps with 10.3% overall yield is described. The synthesis started from commercially available starting materials, d-ribose and (R)-benzyl glycidol. The key reactions involved CBS reduction, Julia–­Kocienski olefination, Horner–Wadsworth–Emmons reaction, and ­Shiina macrolactonization.

A new approach to asymmetric synthesis of (−)-epiquinamide from d-glucose

The asymmetric total synthesis of (−)-epiquinamide has been achieved starting from a 5-iodofuranoside synthon derived from d-glucose. The methods featured Bernet-Vasella reaction followed by Horner-Wadsworth-Emmons (HWE) reaction to provide a new chiral building block diene as the key steps. The bicyclic framework of this quinolizidine was constructed by selective reduction of α,β-unsaturated ester, intramolecular nucleophilic substitution and ring-closing metathesis.

Organocatalytic and Scalable Syntheses of Unsymmetrical 1,2,4,5‐Tetrazines by Thiol‐Containing Promotors

AbstractDespite the growing application of tetrazine bioorthogonal chemistry, it is still challenging to access tetrazines conveniently from easily available materials. Described here is the de novo formation of tetrazine from nitriles and hydrazine hydrate using a broad array of thiol‐containing catalysts, including peptides. Using this facile methodology, the syntheses of 14 unsymmetric tetrazines, containing a range of reactive functional groups, on the gram scale were achieved with satisfactory yields. Using tetrazine methylphosphonate as a building block, a highly efficient Horner–Wadsworth–Emmons reaction was developed for further derivatization under mild reaction conditions. Tetrazine probes with diverse functions can be scalably produced in yields of 87–93 %. This methodology may facilitate the widespread application of tetrazine bioorthogonal chemistry.

Synthesis of 9-CD3-9-cis-retinal cofactor of isorhodopsin

We report the synthesis of 9-CD3-9-cis-retinal via a six-step procedure from β-ionone. The steps involve an initial deuteration of the methyl ketone of β-ionone followed by two consecutive Horner-Wadsworth-Emmons (HWE) coupling reactions and their corresponding DIBAL reductions. A final oxidation of the allylic alcohol of the retinol leads to the target compound. This deuterium labeled retinoid is an important cofactor for studying protein-retinoid interactions in isorhodopsin.

Concise synthesis of 23-hydroxylated vitamin D3 metabolites

Three 23-hydroxylated vitamin D3 derivatives, which are metabolites of 25-hydroxyvitamin D3 produced by CYP24A1 and a related diastereomer, were efficiently synthesized. Each C23 hydroxy unit was constructed by the Claisen condensation reaction with ethyl acetate or the Grignard reaction with 2-methylallymagnesium chloride. Stereochemistry at the C23 position was determined by a modified Mosher’s method. The triene structures were constructed by the Wittig-Horner reaction utilizing the A-ring phosphine oxide moiety.

Synthesis of Indole-, Benzo[ b]thiophene-, and Benzo[ b]selenophene-Based Analogues of the Resveratrol Dimers Viniferifuran and (±)-Dehydroampelopsin B.

A convenient synthetic strategy to obtain viniferifuran and (±)-dehydroampelopsin B analogues based on the heterocyclic cores of indole, benzo[ b]thiophene, and benzo[ b]selenophene is presented. The key transformations utilized in the described syntheses include Sonogashira couplings, Cacchi and alkyne electrophilic cyclizations, Horner-Wadsworth-Emmons (HWE) reaction, chemoselective Suzuki-Miyaura couplings, and acid-promoted intramolecular cyclization to form the seven-membered ring of (±)-dehydroampelopsin B.

Catalytic Process for the Hydroxide-Initiated Reaction of the “Weakly Acidic” Substrate in the Third-Liquid Phase-Transfer Catalytic System

Generation processes of the third phase and the carbanion for Horner−Wadsworth−Emmons (HWE) reaction of the “weakly acidic” substrate in the third−liquid PTC (TLPTC) system were investigated. The third phase was consisted of Et2PO4− (diethyl phosphate anion), Br− and TBA+ (tetrabutylammonium), and the mole of Et2PO4− was 6.65 times of that of TBA+. The true catalyst was the complex of TBA+Et2PO4− and TBAB. Excess Et2PO4− could be associated with TBA+Et2PO4−, resulting the generation of the third phase. The “true” catalyst showed a higher catalytic activity and the reaction equilibrium constant for the third phase cycle was 26−times of that for the organic phase cycle. Results from background reaction, interfacial tension and H−D exchange reaction experiments suggested that the phosphonate were deprotonated by “naked” OH− without help of the catalyst. These novel generation processes of the third phase and the carbanion were the key factors for this efficient TLPTC system.

An Improved and Efficient Synthesis of Panobinostat

An improved and efficient method for the synthesis of panobinostat was developed. The commercially available starting material 4-(chloromethyl)benzaldehyde was converted to ( E)-methyl 3-[4-(chloromethyl)phenyl]acrylate via the Wittig–Horner reaction and was then directly condensed with 2-(2-methyl-1 H-indol-3-yl)ethanamine to afford the key intermediate ( E)-methyl 3-[4-({[2-(2-methyl-1 H-indol-3-yl)ethyl]amino}methyl)phenyl]acrylate in a one-pot synthesis reactor. Subsequently a nucleophilic substitution reaction was carried out smoothly to generate the desired compound. The key intermediate and target compound were characterised by HRMS, 1H NMR and 13C NMR. This procedure is operationally simple and would be more suitable for industrial production.