Horner-Wadsworth-Emmons Research Articles

(E)-Selective Weinreb Amide-Type Horner-Wadsworth-Emmons Reaction: Effect of Reaction Conditions, Substrate Scope, Isolation of a Reactive Magnesium Phosphonoenolate, and Applications.

An iPrMgCl-deprotonating Weinreb amide-type Horner-Wadsworth-Emmons (HWE) reaction was developed, and the effects of diverse reaction conditions, including the base, cation, solvent, and concentration, were investigated to broaden the substrate scope and achieve high (E)-selectivity. The Weinreb amide-type phosphonoenolate generated from iPrMgCl was found to be isolable, stable for at least over a half year, and applicable in the HWE reaction keeping high productivity and selectivity compared with the in situ generated phosphonoenolate. The results prompted us to perform an application study including successive elongation, synthesis of a biscyclopropane, and Weinreb ketone syntheses.

Total Synthesis of Rhizopodin Enabled by a Late-Stage Oxazole Ring Formation Strategy.

Actin stabilizers that are capable of interfering with actin cytoskeleton dynamics play an important role in chemical biology. Rhizopodin, a novel actin stabilizer, affects the actin cytoskeleton at nanomolar concentrations and exhibits potent antiproliferative activities against a range of tumor cell lines with IC50 values in the low nanomolar range. Herein, we report the total synthesis of rhizopodin based on a late-stage oxazole ring formation strategy, whose success demonstrates the feasibility of late-stage oxazole ring formation in the synthesis of complex oxazole containing natural products. Other features of the synthesis include a Nagao aldol reaction, a Suzuki coupling, a Yamaguchi esterification, a modified Robinson-Gabriel synthesis of the oxazoles, and a bidirectional Ba(OH)2-mediated Horner-Wadsworth-Emmons (HWE) reaction.

Microwave-Assisted Hydrolysis of Ethyl Azolylacetates and Cinnamates with K2CO3: Synthesis of Potassium Carboxylates.

In this study, the hydrolysis of ethyl azolylacetates and ethyl cinnamates using K2CO3/ethanol under microwave irradiation was developed. For this purpose, ethyl azolylacetates were first synthesized by nucleophilic substitution between the corresponding azole and ethyl bromoacetate under sonication at 50 °C for 3 h, yielding derivatives with 10-92% chemical yields, while ethyl cinnamates were obtained by a microwave-assisted Horner-Wadsworth-Emmons (HWE) reaction of triethyl phosphonoacetate with a variety of aryl aldehydes at 140 °C for 20 min, yielding derivatives with moderate to high yields (67-98%). Initially, the optimization of the hydrolysis reaction was performed using ethyl pyrazolylacetate as a model starting material while varying the temperature, time, and base equivalents; the best results were achieved by carrying out the reaction at 180 °C for 20 min with 3.0 eq of K2CO3. This simple and greener method facilitated the synthesis of potassium carboxylates in moderate to high yields, 80-98% for azolyl derivatives and 73-98% for cinnamate derivatives. The structures of all potassium carboxylates were confirmed by FTIR, 1H, 13C NMR, and HRMS.

Synthesis of 5-(4-Formylphenyl)barbituric Acid to Access Enolizable Chromophoric Barbituric Acids

AbstractBarbituric acids mono-substituted at the 5-position show keto–enol tautomerism. In the keto form, conjugation to an aryl substituent is interrupted due to the sp³-hybridized carbon atom at the 5-position of barbituric acid. The enol form generates a conjugated π-system to the aryl substituent and acts as an electron-donating group. If the aryl substituent is electron-deficient, a push-pull system is generated that shows typical UV/Vis absorption. These types of compounds are difficult to access synthetically due to their intrinsic convertibility. The synthesis of barbituric acids with a 4-formylphenyl functionality at the 5-position is reported. This compound, 5-(4-formylphenyl)barbituric acid, could be used to introduce extended π-systems with electron-withdrawing groups in great variety by simple condensation reactions. We demonstrate this by a Horner–Wadsworth–Emmons reaction that forms the enolizable dye (E)-5-(4-(4-nitrostyryl)phenyl)barbituric acid.

A Novel Synthesis and Quantitation Route of Belinostat

Introduction: This research article describes the production, quantification, and purification of belinostat from 3-nitrobenzaldehyde as the starting material. A cascade-step process produces higher yields when compared to all previous existing methodologies. Method: The procedure involved the following: Horner–Wadsworth–Emmons (HWE) reaction of aromatic aldehydes with triethylphosphonoacetate in the presence of potassium carbonate, reduction of the nitro group to the amino group, sulfochlorination by thionyl chloride, aniline-mediated sulfonamidation, and hydroxylamine amidation as the last step. Results: The prepared solid belinostat was purified, and an acceptable yield of 56-60% was obtained. Conclusion: The approach has several key benefits, including low-cost beginning materials, straightforward techniques, safer and more reliable results, and substantial environmental advantages.

Synthesis of Methyl 2-[Bis(benzylthio)phosphoryl]acetate as a Novel Horner–Wadsworth–Emmons-Type Reagent and Its Application to the Diastereodivergent Synthesis of (E)- and (Z)-α,β-Unsaturated Esters

AbstractMethyl 2-[bis(benzylthio)phosphoryl]acetate has proven to be an efficient Horner–Wadsworth–Emmons (HWE)-type reagent for the diastereodivergent synthesis of (E)- and (Z)-α,β-unsaturated esters. Under the conditions of excess NaHMDS relative to the HWE-type reagent, the HWE-type reactions of methyl 2-[bis(benzylthio)phosphoryl]acetate with various aldehydes afforded the corresponding α,β-unsaturated esters in an E-selective manner in up to 100:0 E/Z ratio. However, when an excess of the HWE-type reagent was used relative to NaHMDS, the stereoselectivity of the HWE-type reactions was dramatically changed from E to Z, yielding an E/Z ratio of up to 2:98.

Horner–Wadsworth–Emmons olefination of proteins and glycoproteins

Chemo-selective modifications of proteins are fundamental to the advancement of biological and pharmaceutical sciences. The search for biocompatible chemical reactions has prompted us to investigate Horner–Wadsworth–Emmons (HWE) olefinations, iconic reactions in organic synthesis that would give rise to new selective protein olefinations. Our choice of HWE olefinations was inspired by the growing number of methods for generating aldehydes as transient reactive groups in proteins and the potential for mild and simple reaction conditions. Here we show that HWE olefination reactions on aldehydes, produced by both chemical and enzymatic methods, are compatible with physiological conditions and highly selective in small and large proteins, including therapeutic antibodies and stable recombinant proteins exemplified by green fluorescent protein. Reaction kinetics can be fine-tuned over orders of magnitude both by judicious use of substituents and pH regulation. The electrophilic nature of the HWE olefination products can be tuned to allow for subsequent nucleophilic additions, including thiol- and phospha-Michael additions. Our results demonstrate that HWE olefination of aldehydes in proteins provides efficient and selective bioconjugation chemistries that are orthogonal to existing methods.

Design, synthesis, and biological activity of D-bishomo-1α,25-dihydroxyvitamin D3 analogs and their crystal structures with the vitamin D nuclear receptor

The biologically active metabolite of vitamin D3 - calcitriol – is a hormone involved in the regulation of calcium-phosphate homeostasis, immunological processes and cell differentiation, being therefore essential for the proper functioning of the human body. This suggests many applications of this steroid in the treatment of diseases such as rickets, psoriasis and some cancers. Unfortunately, using therapeutic doses of calcitriol is associated with high concentrations of this compound which causes hypercalcemia. For this reason, new calcitriol analogs are constantly sought, devoid of calcemic effects but maintaining its beneficial properties. In this study, we present the synthesis of vitamin D derivatives characterized by an enlarged (seven-membered) ring D. Preparation of the designed vitamin D compounds required separate syntheses of crucial building blocks (C/D-rings fragments with side chain and rings A) which were combined by different methods, including Wittig-Horner reaction and Suzuki coupling. Biological activities of the target vitamin D analogs were assessed both in vitro and in vivo, demonstrating their significant potency compared to the natural hormone. Furthermore, the successful crystallization of these compounds with the vitamin D receptor (VDR) enabled us to investigate additional molecular interactions with this protein.

Solvent-Free Synthesis of α-Cyanophosphonates from β-Nitro­styrenes by Using a Deep-Eutectic Solvent Catalyst

Abstractα-Cyanophosphonates, which are useful reagents for the Horner–Wittig reaction, were synthesized under solvent-free conditions by using a choline chloride–zinc chloride deep-eutectic solvent (DES) as a catalyst. This is only the second report on the synthesis of these compounds. In the previous report, diethyl trimethylsilyl phosphite was used as a reagent and TiCl4 as a catalyst, whereas in this study, both the reagent (triphenylphosphine) and the catalyst (choline chloride–zinc chloride DES) are cheaper, more readily available, and less harmful than those used in the previous work. Moreover, the process involves an interesting cascade reaction between a β-nitrostyrene and two equivalents of triphenyl phosphite, leading to the desired product by a new synthetic route. The products can be used in the pharmaceutical and agricultural industries, in addition to their synthetic applications in the preparation of α,β-unsaturated nitriles. The reactions were completed on using 20 mol% of DES at 80 °C in six hours. Ten different β-nitrostyrenes were synthesized in yields of 55–87% after purification. β-Nitrostyrenes containing electron-donating groups showed higher yields. The reaction failed when aliphatic or heteroaromatic nitroalkenes or β-nitrostyrenes with electron-withdrawing substituents were employed. Finally, three plausible mechanistic routes are proposed for the reaction, starting with the nucleophilic addition of triphenyl phosphite to the carbon, nitrogen, or oxygen atom in the α-position.

Asymmetric synthesis of the fully functionalized six-membered A-ring of siphonol A.

A synthetic study toward the construction of the fully functionalized six-membered A-ring of siphonol A is described. The salient features include the introduction of a six-membered ring system through a HWE reaction, the construction of a stereocenter at C5 via a hetero-Diels-Alder reaction, and the installation of the fully functionalized six-membered A-ring of siphonol A through photolytic decarboxylation.

Asymmetric Synthesis of Arboduridine

AbstractThe first asymmetric total synthesis of the monoterpenoid indole alkaloid arboduridine has been accomplished. The tricyclic A/B/D ring system was constructed by an enantioselective Michael reaction followed by intramolecular nucleophilic addition. Intramolecular α‐amination of a ketone forged the piperidine ring, while a Horner–Wadsworth–Emmons (HWE) reaction was used to form the pyrrolidine ring. A reduction cyclization cascade led to formation of the tetrahydrofuran ring.

Asymmetric Synthesis of Arboduridine.

The first asymmetric total synthesis of the monoterpenoid indole alkaloid arboduridine has been accomplished. The tricyclic A/B/D ring system was constructed by an enantioselective Michael reaction followed by intramolecular nucleophilic addition. Intramolecular α-amination of a ketone forged the piperidine ring, while a Horner-Wadsworth-Emmons (HWE) reaction was used to form the pyrrolidine ring. A reduction cyclization cascade led to formation of the tetrahydrofuran ring.

Divergent and Stereoselective Synthesis of Ustusal A, (-)-Albrassitriol, and Elegansin D.

The first synthesis of ustusal A as well as expeditious access to (-)-albrassitriol is described as featuring a singlet oxygen [4 + 2] cycloaddition, achieving the desired stereoselectivity for the 1,4-cis-hydroxyl groups. Transformation of (+)-sclareolide to III followed by a key Horner-Wadsworth-Emmons (HWE) reaction and stereospecific allylic oxidation facilitated the first synthesis of elegansin D. The biological evaluation of these natural products together with seven elegansin D analogues was performed, among which several elegansin D analogues exhibited potential anticancer activity against liver cancer HepG2 cells (IC50 = 11.99-25.58 μM) with low cytotoxicity on normal liver HL7702 cells (IC50 > 100 μM).

A biocompatible Horner-Wadsworth-Emmons (HWE) reaction triggered by a bioorthogonal proximity-induced platform

Here, we present a novel bioorthogonal platform that enables precise positioning of attached moieties in close proximity, thereby facilitating the discovery and optimization of biocompatible reactions. Using this platform, we achieve a Horner-Wadsworth-Emmons (HWE) reaction under physiological conditions, generating a fluorophore in situ with a yield of up to 93%. This proximity platform should facilitate the discovery of various types of biocompatible reactions, making it a versatile tool for biomedical applications.

Natural product-inspired synthesis of coumarin-chalcone hybrids as potential anti-breast cancer agents.

Twelve novel neo-tanshinlactone-chalcone hybrid molecules were constructed through a versatile methodology involving the Horner-Wadsworth-Emmons (HWE) olefination of 4-formyl-2H-benzo [h]chromen-2-ones and phosphonic acid diethyl esters, as the key step, and evaluated for anticancer activity against a series of four breast cancers and their related cell lines, viz. MCF-7 (ER + ve), MDA-MB-231 (ER-ve), HeLa (cervical cancer), and Ishikawa (endometrial cancer). The title compounds showed excellent to moderate in vitro anti-cancer activity in a range of 6.8-19.2µM (IC50). Compounds 30 (IC50 = 6.8µM and MCF-7; IC50 = 8.5µM and MDA-MB-231) and 31 (IC50 = 14.4 µM and MCF-7; IC50 = 15.7µM and MDA-MB-231) exhibited the best activity with compound 30 showing more potent activity than the standard drug tamoxifen. Compound 30 demonstrated a strong binding affinity with tumor necrosis factor α (TNF-α) in molecular docking studies. This is significant because TNFα is linked to MCF-7 cancer cell lines, and it enhances luminal breast cancer cell proliferation by upregulating aromatase. Additionally, virtual ADMET studies confirmed that hybrid compounds 30 and 31 met Lipinski's rule; displayed high bioavailability, excellent oral absorption, favorable albumin interactions, and strong penetration capabilities; and improved blood-brain barrier crossing. Based on the aforementioned results, compound 30 has been identified as a potential anti-breast cancer lead molecule.

Design, synthesis, and cytotoxic activity of pyridine-based stilbenes

In the present study, three series of 35 pyridine-based stilbenes include 10 new compounds prepared by Horner-Wadsworth-Emmons (HWE) reaction were assayed for cytotoxic activities toward two tumoral cell lines (K562 and MDA-MB-231) and one non-tumoral cell line (L-02). The bioassay results indicated that hybrid stilbenes formed at the C-3 position of pyridine displayed stronger antiproliferative activities against K562 cells and C-4 pyridine-based stilbenes showed broad-spectrum cytotoxic effects. Among them, C-3 pyridine-based stilbene PS2g bearing 2,6-dimethoxy possessed extremely potent antiproliferative activity with IC50 values 1.46 µM against K562 cells, along with excellent selectivity towards normal L-02 cells. In summary, the present study contributes to the development of natural stilbene-based derivatives as antitumor agents and PS2g may serve as a promising lead for the treatment of chronic myeloid leukemia (CML) worthy further investigation.

Synthesis and Structure-Activity Relationship Studies of C(13)-Desmethylene-(-)-Zampanolide Analogs.

We describe the synthesis and biochemical and cellular profiling of five partially reduced or demethylated analogs of the marine macrolide (-)-zampanolide (ZMP). These analogs were derived from 13-desmethylene-(-)-zampanolide (DM-ZMP), which is an equally potent cancer cell growth inhibitor as ZMP. Key steps in the synthesis of all compounds were the formation of the dioxabicyclo[15.3.1]heneicosane core by an intramolecular HWE reaction (67%-95% yield) and a stereoselective aza-aldol reaction with an (S)-BINOL-derived sorbamide transfer complex, to establish the C(20) stereocenter (24%-71% yield). As the sole exception, for the 5-desmethyl macrocycle, ring-closure relied on macrolactonization; however, elaboration of the macrocyclization product into the corresponding zampanolide analog was unsuccessful. Compared to DM-ZMP, all modifications led to reduced cellular activity and lowered microtubule-binding affinity, albeit to a different extent. For compounds incorporating the reactive enone moiety of ZMP, IC50's for cancer cell growth inhibition varied between 5 nM and 133 nM, compared to 1 nM to 12 nM for DM-ZMP. Reduction of the enone double bond led to a several hundred-fold loss in growth inhibition. The cellular potency of 2,3-dihydro-13-desmethylene zampanolide, as the most potent analog identified, remained within a 9-fold range of that of DM-ZMP.

Synthesis of the proposed structure of enhypyrazinone A, a rare marine-derived 3,5,6-tri-substituted pyrazinone secondary metabolite

Herein, we report the first total synthesis of enhypyrazinone A, a rare tri-substituted pyrazinone secondary metabolite that is isolated from the marine-derived myxobacterium Enhygromyxa sp. The key features of the synthesis involve a Horner-Wadsworth-Emmons (HWE) olefination to provide a crucial C5-substituted (E)-styryl group and the construction of a 3,5,6-tri-substituted pyrazinone skeleton from a highly functionalized dipeptide intermediate via pyridine-promoted cyclization and subsequent spontaneous aerobic oxidation. Although the 13C NMR spectra of the synthetic enhypyrazinone A slightly differed from those reported previously, the structure was confirmed by comprehensive 2D NMR analysis, including 1H–1H COSY, 1H–13C HSQC, and 1H–13C HMBC. Our concise and straightforward synthetic route provides the proposed structure of enhypyrazinone A with eight linear steps in 27.4% overall yield from commercially available Boc-Trp-OMe.

Gram‐Scale Synthesis of Chain‐Deuterated Sphingosine and Its Derivatization to Produce Ceramide, Sphinganine and Sphingosine‐1‐phosphate

AbstractSphingosine plays crucial roles in various cellular functions. Deuterated molecules are widely used as the important tools to explore the structure, property, and function of biochemical materials. We here report a gram‐scale synthesis of sphingosines with different deuterated chains. The synthesis started from different protiated fatty acids, which underwent hydrothermal platinum‐catalyzed hydrogen/deuterium (H/D) exchange to produce the deuterated chains with different length. The Horner–Wadsworth–Emmons (HWE) coupling of a chiral amino acid derivative with the deuterated chains generated the unsaturated ketone precursors. The following stereoselective reduction via cyclic Felkin–Anh transition led to the desired anti‐amino alcohol geometry. This efficient protocol enabled the gram‐scale synthesis of the chain‐deuterated sphingosines. The subsequent synthesis of the chain‐deuterated derivatives, i. e. ceramide, sphinganine and sphingosine‐1‐phosphate, is also described. Their deuterium content was simultaneously characterized by 1H NMR and high‐resolution mass spectrum (HRMS).

Digitizing chemical discovery with a Bayesian explorer for interpreting reactivity data

Interpreting the outcome of chemistry experiments consistently is slow and frequently introduces unwanted hidden bias. This difficulty limits the scale of collectable data and often leads to exclusion of negative results, which severely limits progress in the field. What is needed is a way to standardize the discovery process and accelerate the interpretation of high-dimensional data aided by the expert chemist's intuition. We demonstrate a digital Oracle that interprets chemical reactivity using probability. By carrying out >500 reactions covering a large space and retaining both the positive and negative results, the Oracle was able to rediscover eight historically important reactions including the aldol condensation, Buchwald-Hartwig amination, Heck, Mannich, Sonogashira, Suzuki, Wittig, and Wittig-Horner reactions. This paradigm for decoding reactivity validates and formalizes the expert chemist's experience and intuition, providing a quantitative criterion of discovery scalable to all available experimental data.