Horner Wadsworth Emmons Reagents Research Articles

Synthesis and Cytotoxic Evaluation of 3-Methylidenechroman-4-ones.

In the search for new anticancer agents, a library of variously substituted 3-methylidenechroman-4-ones was synthesized using Horner–Wadsworth–Emmons methodology. Acylation of diethyl methylphosphonate with selected ethyl salicylates furnished 3-diethoxyphosphorylchromen-4-ones which were next used as Michael acceptors in the reaction with various Grignard reagents. The adducts were obtained as the mixtures of trans and cis diastereoisomers along with a small amount of enol forms. Their relative configuration and preferred conformation were established by NMR analysis. The adducts turned up to be effective Horner–Wadsworth–Emmons reagents giving 2-substituted 3-methylidenechroman-4-ones, which were then tested for their possible cytotoxic activity against two leukemia cell lines, HL-60 and NALM-6, and against MCF-7 breast cancer cell line. All new compounds (14a–o) were highly cytotoxic for the leukemic cells and showed a moderate or weak effect on MCF-7 cells. Analog 14d exhibited the highest growth inhibitory activity and was more potent than carboplatin against HL-60 (IC50 = 1.46 ± 0.16 µM) and NALM-6 (IC50 = 0.50 ± 0.05 µM) cells. Further tests showed that 14d induced apoptosis in NALM-6 cells, which was mediated mostly through the extrinsic pathway.

Enantioselective synthesis of 5-methylidenedihydrouracils as potential anticancer agents

An efficient, versatile, enantioselective synthesis of 1,3-disubstituted and 1,3,6-trisubstituted 5-methylidenedihydrouracils applying Horner-Wadsworth Emmons methodology was developed. Starting 1,3-disubstituted 5-diethoxyphosphoryluracils were subjected to reduction of the double bond or addition of various Grignard reagents and obtained Horner-Wadsworth Emmons reagents were used for the olefination of formaldehyde. Enantioselective synthesis of 1,3,6-trisubstituted 5-methylidenedihydrouracils was accomplished by introducing (R,R)- or (S,S)-di(1-phenylethylamino)phosphoryl groups as chiral auxiliary. Additions of Grignard reagents in the presence of these groups were highly and complimentary diastereoselective (de ∼ 80%). Further separation of the diastereomeric mixtures by column chromatography enabled synthesis of (R)- and (S)-1,3,6-trisubstituted-5-methylidenedihydrouracils with ee ≥ 98%. Furthermore, absolute configuration of the adducts and final products was established using single crystal X-ray analysis. Stereochemical course of the addition reactions is also discussed.

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 ...

Facile Two-Step Synthesis of Methyl Bis(2,2,2-trifluoroethyl)phosphonoacetate by Exploiting Garegg–Samuelsson Reaction Conditions

A facile two-step synthesis of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate (Still–Gennari reagent) has been developed by exploiting Garegg–Samuelsson reaction conditions. Starting from trimethyl phosphonoacetate, Still–Gennari reagent was prepared in 94% yield via methyl 2-{bis[(trimethylsilyl)oxy]phosphoryl}acetate intermediate. This synthetic procedure was also used to prepare some kinds of Horner–Wadsworth–Emmons reagents and related compounds.

Synthesis of Fluorine-Containing Analogues of 1-Lysoglycerophospholipids via Horner–Wadsworth–Emmons Reaction

An efficient method of synthesizing fluorine-containing analogues of 1-lysoglycerophospholipids (1-LPLs) by introducing a palmitoyl moiety starting from bis(2,2,2-trifluoroethyl)phosphonoacetate (Still–Gennari reagent) is described. The method effectively employs Horner–Wadsworth–Emmons reagents as masked 1-LPL derivatives to prepare a series of analogues of 1-lysophosphatidic acid (1-LPA), 1-lysophosphatidylethanolamine (1-LPE), and 1-lysophosphatidylcholine (1-LPC).

ChemInform Abstract: Convenient Stereoselective Synthesis of β‐Perfluoroalkyl α,β‐Unsaturated Esters via Horner—Wadsworth—Emmons Reactions.

AbstractVarious title esters are obtained with high (E)‐stereoselectivity by condensation reactions of in situ produced halogenated ketones with Horner—Wadsworth—Emmons reagents.

A New Synthesis of Phosphorane Ylide Precursors to Vicinal Tricarbonyls from Alkyl Halides Utilizing a Novel Phenylsulfonyl Reagent

Due to the presence in many bioactive natural products such as FK-506, rapamycin, eurystatin, and cyclotryprostatin, and their usefulness in the synthesis of heterocyclic compounds, the vicinal tricarbonyls have been attractive and challenging research topics for synthetic chemists. Although Wasserman’s synthetic approach to vicinal tricarbonyls has been extensively used in the synthesis of complex compounds, it has a limitation that the phosphorane ylide 2, the key precursors to vicinal tricarbonyls, should be prepared only from carboxylic acids or acid chlorides (Scheme 1). In previous studies we have reported new approaches to 2 from carbonyl compounds using a new Horner-WadsworthEmmons reagent, and from alkyl halides using a new sulfinyl reagent to overcome the above-mentioned limitation. In continuation of our study, we have recently developed a unique approach to α-keto cyanophosphorane ylides, the key precursors to α-keto amide/ester units in Wasserman’s protocol, from alkyl halides using a novel phenylsulfonyl reagent. As an extension of this chameleonic sulfone chemistry for the synthesis of phosphorene ylide precursors 2’ from chemicals other than carboxylic acids and acid chlorides, we herein wish to report a further method for forming 2’ from alkyl halides using a new phenylsulfonyl reagent 4 as the key reagent (Scheme 2).

A novel synthetic approach to glycerophospholipids via Horner–Wadsworth–Emmons reaction of mixed phosphonoacetate

A novel synthetic approach to glycerophospholipids featuring the use of Horner–Wadsworth–Emmons reagents as masked glycerophospholipids has been developed. Based on this method, phosphatidic acid (PA), phosphatidylethanolamine (PE), and phosphatidylcholine (PC) containing palmitoyl moieties were readily synthesized from a mixed phosphonoacetate as a common key intermediate.

Rhenium-catalyzed synthesis of 2H-1,2-oxaphosphorin 2-oxides via the regio- and stereoselective addition reaction of β-keto phosphonates with alkynes.

Treatment of β-keto phosphonates (Horner-Wadsworth-Emmons reagents) with terminal alkynes in the presence of a rhenium catalyst gave 2H-1,2-oxaphosphorin 2-oxides with various substitution patterns. The reaction proceeds via two consecutive processes: cleavage of a carbon-carbon σ-bond of the β-keto phosphonate with insertion of the alkyne in a regio- and stereoselective manner, followed by cyclization of the resulting δ-phosphonyl α,β-unsaturated ketone yielding the 2H-1,2-oxaphosphorin 2-oxide. Horner-Wadsworth-Emmons reagents were found to add to nonpolar unsaturated compounds under neutral conditions.

ChemInform Abstract: One‐Pot, Two‐Step Conversion of Aldehydes to Phosphonyl‐ and Sulfonylpyrazoles Using Bestmann—Ohira Reagent.

AbstractThe Bestmann—Ohira reagent (Ia) is employed traditionally as a Horner—Wadsworth—Emmons reagent in the conversion of aldehydes to the terminal acetylene intermediates (III).

Efficient Synthesis of Anhydrorhodovibrin and Analogues

The synthesis of anhydrorhodovibrin and two analogues has been achieved in a highly efficient manner using a new Horner–Wadsworth–Emmons reagent bearing the Weinreb amide.

Dipolar Sesquifulvalene Compounds with (Tetraaryl-η4-cyclobutadiene)(η5- cyclopentadienediyl)cobalt(I) Complex Units as Electron Donors

Mononuclear monohydro sequifulvalene complexes of cobalt and their vinylogous derivatives [(Ar4CBD)Co(Cp-Z-C7H7)] (Ar4CBD = C4Ar4; Ar = p-X-C6H4; X = H, Z = – (4); X = H, −C2H2– (9a); X = Cl, Z = −C2H2– (9b); X = Me, Z = −C2H2– (9c); X = OMe, Z = −C2H2– (9d); X = NMe2, Z = −C2H2– (9e); X = H, Z = −(C2H2)2– (10); X = H, Z = −(C2H2)3– (11)) were synthesized and transformed by hydride abstraction to the corresponding dipolar sesquifulvalene complexes of [(Ar4CBD)Co(Cp-Z-C7H6)]+ (Ar4CBD = C4Ar4; Ar = p-X-C6H4; X = H, Z = – (5); X = H, Z = −C2H2– (12a); X = Cl, Z = −C2H2– (12b); X = Me, Z = −C2H2– (12c); X = H, Z = −(C2H2)2– (13)) featuring a (tetraaryl-η4-cyclobutadiene)(η5-cyclopentadienediyl)cobalt(I) sandwich complex as an electron donor and the cationic tropylium part as an electron acceptor. Hydride abstraction to form the complexes [(Ar4-η4-CBD)Co{(η5-C5H4)Z(C7H6)]+ (Ar = p-C6H4X; X = OMe, NMe2; Z = −C2H2−) and [(Ar4-η4-CBD)Co{(η5-C5H4)Z(C7H6)}]+ (Ar = C6H5; Z = −(C2H2)3– (14)) failed and led to decomposition. The mononuclear archetypal sesquifulvalene complex 5 was obtained by nucleophilic addition of the monolithiated complex (Ar4CBD)Co(CpLi) (3) to tropylium cation and subsequent hydride abstraction from the seven-membered ring. The vinylogous derivatives 9a–e, 10, and 11 were prepared by Horner–Wadsworth–Emmons (HWE) reactions of the suitable carbaldehydes (Ar4CBD)Co(Cp-Z-CHO) (Z = −(C2H2)n−) with the HWE reagent cyclohepta-1′,3′,5′-trien-1′-ylmethylphosphonate diethyl ester in a phase transfer catalyzed reaction. The donor–acceptor interaction was studied by means of 1H and 13C NMR and UV–vis spectroscopy, cyclic voltammetry, X-ray structure determination, and hyper-Rayleigh scattering (HRS) measurements. For analysis of electronic excitations DFT calculations were performed on the complexes, revealing the cyclobutadiene metal complex fragment to be the donor and the metal complex Cp-bridge-cycloheptatrienylium fragment to be the acceptor.

Synthesis and biological evaluation of α-methylidene-δ-lactones with 3,4-dihydrocoumarin skeleton

A series of new 3-methylidenechroman-2-ones bearing various aromatic moieties and various substituents at position 4 were synthesized in a three step reaction sequence. Friedel–Crafts alkylation of phenols or naphthols using ethyl 3-methoxy-2-diethoxyphosphorylacrylate in the presence of trifluoromethanesulphonic acid gave 3-diethoxyphosphorylchromen-2-ones. These compounds were employed as Michael acceptors in the reaction with Grignard reagents to give adducts which were finally used as Horner–Wadsworth–Emmons reagents for the olefination of formaldehyde. All obtained 3-methylidenechroman-2-ones were tested against two human leukemia cell lines NALM-6 and HL-60 as well as MCF-7 breast cancer and HT-29 colon cancer adenocarcinomas. Several obtained methylidenechromanones displayed high cytotoxic activity with IC50 values below 1μM, mainly against leukemia and MCF-7 cell lines. Investigation of structure–activity relationships revealed that the presence of additional, ortho-fused benzene ring and n-butyl or i-propyl group in position 4 enhances the activity. Selected methylidenechromanones were also tested on normal human umbilical vein endothelial cells (HUVEC) and chromanone 14o was found to be eightfold more toxic against MCF-7 than normal cells. Furthermore, antimicrobial assays revealed that chromanone 14n is highly active and bactericidal at concentration equal to MIC or 2MIC against nosocomial and community-associated staphylococci (MRSA) which are resistant to most or all available therapeutic classes of antimicrobial drugs.

Oxidative functionalization of benzylic C–H bonds by DDQ

C–H activation of the methyl group of toluene and related ArCH3 derivatives by 2,3-dichloro-4,5-dicyano-1,4-benzoquinone (DDQ) gives insertion products, ArCH2O[C6Cl2(CN)2]OH via a rate-determining hydride abstraction by DDQ. The resulting benzylic ether can undergo reactions with phosphines to give benzylic phosphonium salts (Wittig reagents) and with phosphites to give phosphonate esters (Horner–Wadsworth–Emmons reagents).

ChemInform Abstract: Enantioselective Mannich Reaction of a Highly Reactive Horner—Wadsworth—Emmons Reagent with Imines Catalyzed by a Bifunctional Thiourea.

AbstractN‐Acyl pyrrole phosphonates (II) are highly reactive nucleophiles for the asymmetric Horner—Wadsworth—Emmons reaction.

Comparing and taming the reactivity of HWE and Wittig reagents with cyclic hemiacetals

A practical solution to the formation of mixtures of E/ Z and open/cyclic isomers in the reaction of (2 R,4 S)-4-hydroxy-2-methylpentanal (as its hemiacetal, a lactol) with conjugated phosphoranes (stabilised Wittig reagents) and Horner–Wadsworth–Emmons reagents is disclosed. The HWE reaction has a strong bias to give oxolanes. On the other hand, stabilised Wittig reagents give unsaturated carboxyl derivatives of configuration E (major) and oxolanes (minor); the latter can be avoided by addition of CF 3CH 2OH or using morpholine amide phosphorane.

Correction to Preparation of α,β-Unsaturated Diazoketones Employing a Horner–Wadsworth–Emmons Reagent

Correction to Preparation of α,β-Unsaturated Diazoketones Employing a Horner–Wadsworth–Emmons Reagent

ChemInform Abstract: A New Synthesis of Triphenylhosphorane Ylide Precursors to α‐Keto Amide/Ester and Tricarbonyl Units via Horner—Wadsworth—Emmons Reaction.

AbstractNewly developed Horner—Wadsworth—Emmons reagents (III) readily condense with various carbonyl compounds to afford the corresponding β,γ‐unsaturated α‐keto triphenylphosphoran ylides of type (V) or (VIII) which can easily be reduced to the corresponding β,γ‐saturated α‐keto triphenylphosphoran ylides of type (VI) or (IX).

ChemInform Abstract: Horner—Wadsworth—Emmons Reagents as Azomethine Ylide Analogues: Pyrrole Synthesis via [3 + 2] Cycloaddition.

AbstractThe three‐component Arbuzov reaction of imines, acid chlorides and phosphites creates a phosphonate precursor which acts as 1,3‐dipole.

Enantioselective Mannich reaction of a highly reactive Horner–Wadsworth–Emmons reagent with imines catalyzed by a bifunctional thiourea

N-acyl pyrrole phosphonates were identified as a class of highly reactive HWE reagents. The asymmetric addition of the present HWE reagents to N-carbamoyl imines generated in situ was achieved. The corresponding Mannich adducts can be further transformed to aza-MBH type products in good to excellent enantioselectivities.