Intramolecular oxa-Michael Addition Research Articles

C-Dimethylated Flavones as Possible Potential Anti-Tubercular and Anticancer Agents.

The present investigation describes an intramolecular Oxa-Michael addition of penta-substituted phenols to the enone of the tether in the presence of iodine as the oxidizing agent. Ten C-Dimethylated flavones with moderate to good yields (10a-j, 60-89 %) were isolated by heating the corresponding C-dimethylated chalcones using iodine in DMSO. Using the Microplate Alamar Blue test (MABA) technique, the drugs' quantitative drug susceptibility against the H37Rv strain of replicating Mycobacterium TB was determined. The sensitivity of two of the developed compounds (10e, 10h) was up to 6.25 g/mL. The human lung adenocarcinoma cell lines (A549) were used in the anticancer study, which was carried out using the MTT cell proliferation assay. In A549 cell lines, four flavones demonstrated anticancer activity with IC50 values between 39 and 48 μM. The C-dimethylated flavones, 10b (3,4-dimethoxy), 10c (2,3,4-trimethoxy), 10e (p-fluoro) and 10g (N-methyl indole) substitutions on ring 'B' showed good anticancer activity with IC50 values 39.17, 39.21, 48.43 and 43.48 μM, respectively. The compounds 10b, 10c, 10d, 10e, and 10i had improved binding and interaction profiles among all the compounds examined during the current In Silico research, as shown by the docking simulations against two targets EGFR and MTB MurI.

Albumin-catalysed synthesis of flavanones

Flavanones are a family of phytochemicals that have regained importance over the last decade due to their diverse biological activity. The conventional building of the flavanone skeleton is accomplished through a Claisen-Schmidt condensation followed by an intramolecular oxa-Michael addition, but the involved strong basic pH favours side reactions and affects flavanone yield. This work presents a mild access to flavanones based on a sustainable catalyst, bovine serum albumin (BSA), which is a promiscuous protein. BSA catalysed the reaction between a set of 2 ´ -hydroxyacetophenones and benzaldehydes in methanol at 60 °C to give the corresponding flavanones in 58–90% conversions. Experiments showed that BSA promotes the Claisen-Schmidt step as well as accelerates the subsequent oxa-Michael addition. Besides, BSA-catalysed reaction of acetophenone and benzaldehyde was studied, which afforded the Michael adduct 1,3,5-triphenylpentane-1,5-dione (85% conversion). On the whole, the herein reported results expand the potential of BSA as a mild and sustainable catalyst in organic synthesis.

Stereoselective Synthesis of Acyclic Skeleton of Boscartin A

AbstractStereoselective synthesis of key acyclic skeleton of structurally challenging and biologically active boscartin A possessing six stereogenic centers, among which three are tertiary, has been achieved for the first time. The synthetic study comprises the Sharpless asymmetric epoxidation (SAE) followed by stereoselective epoxide opening for installation of C-11 and C-12 centers, Meyer–Schuster rearrangement followed by intramolecular oxa-Michael addition for construction of C-1 center, SAE followed by CBS reduction and subsequent cycloetherification for stereoselective generation of C-3, C-4, and C-7 centers, Gilman reaction for introduction of C-9 olefin and Grignard reaction for installation of C-8 olefin.

Towards understanding oxygen heterocycle-forming biocatalysts: a selectivity study of the pyran synthase PedPS7.

Intramolecular oxa-Michael addition-catalysing cyclases are widespread in polyketide biosynthetic pathways. Although they have significant potential in biotechnology and chemoenzymatic synthesis of chiral heterocycles, they have only scarcely been studied. Here, we present detailed investigations on the selectivity profile of the pyran synthase PedPS7 showing that it combines broad substrate tolerance with high selectivity for the formation of up to two new stereocentres and relaxed precursor stereoisomer discrimination. Two of the four possible tetrahydropyran stereoisomers are reliably accessible by this enzyme. The results indicate fundamental differences between the individual subtypes of intramolecular oxa-Michael addition-catalysing cyclases.

An intramolecular oxa-Michael addition on prebuilt β-lactam tethered α, β-unsaturated ester: A remarkable synthesis of a unique scaffold of 2,3-fused β-lactam-1,4-dioxepane

An expeditious base assisted highly diastereoselective intramolecular oxy-Michael addition reaction in the synthesis of enantiomerically pure 1,4-dioxepane fused β-lactam has been described. This present study has been portrayed a rapid intramolecular 7-exo-trig oxy-Michael reaction involving chemoselective nucleophilic addition of 20 alcohol of the vic-diols to an α β-unsaturated ester. Furthermore, the developed methodology elaborates an extremely atom-economical approach in constructing the C–O bond in stereoselective fashion under mild reaction conditions.

Design and synthesis of dual active neovibsanin derivatives based on a chemical structure merging method

A hybrid compound consisting of neovibsanin and trans-banglene was designed according to a structure merging method and synthesized via a sequence of key steps including a Diels–Alder cycloaddition, stereoselective alkynylation, and intramolecular oxa-Michael addition reaction. The biological activity of the synthetized acetal compound and its hemiacetal analogue was investigated in PC12 cells. These studies revealed that the designed hybrid compounds displayed neuritogenic activity. Furthermore, a relatively strong neurite outgrowth promoting activity was observed in the presence of NGF. These results suggest that the designed hybrid compound exhibited a dual activity.

Organocatalytic Approach for Assembling Flavanones via a Cascade 1,4-Conjugate Addition/oxa-Michael Addition between Propargylamines with Water.

A DBU-catalyzed one-pot cascade reaction of propargylamines and water for the synthesis of flavanones has been developed. This process proceeds via a sequence of 1,4-conjugate addition of water to alkynyl o-quinone methide (o-AQM), followed by the alkyne-allene isomerization and subsequent intramolecular oxa-Michael addition. This strategy provides a convenient method for accessing a broad range of flavanones in good to excellent yields with good functional-group tolerance, in particular, the reactive halo functional groups.

Synthesis of the 8,19-Epoxysteroid Eurysterol A.

We report the first chemical synthesis of eurysterol A, a cytotoxic and antifungal marine steroidal sulfate with a unique C8−C19 oxy‐bridged cholestane skeleton. After C19 hydroxylation of cholesteryl acetate, used as an inexpensive commercial starting material, the challenging oxidative functionalization of ring B was achieved by two different routes to set up a 5α‐hydroxy‐7‐en‐6‐one moiety. As a key step, an intramolecular oxa‐Michael addition was exploited to close the oxy‐bridge (8β,19‐epoxy unit). DFT calculations show this reversible transformation being exergonic by about −30 kJ mol−1. Along the optimized (scalable) synthetic sequence, the target natural product was obtained in only 11 steps in 5 % overall yield. In addition, an access to (isomeric) 7β,19‐epoxy steroids with a previously unknown pentacyclic ring system was discovered.

Synthesis and Evaluation of the Lifespan-Extension Properties of Oleracones D–F, Antioxidative Flavonoids from Portulaca oleracea L.

Plant-derived antioxidants have been widely used as supplementary health foods, as well as having been regarded as drug candidates for aging and aging-associated diseases. Oleracones, a novel series of flavonoids isolated from Portulaca oleracea L., possess potent antioxidative activities and are expected to exhibit therapeutic potential on the aging process. The current paper describes the concise sequential synthesis of oleracones D–F. Oleracones D and F were efficiently synthesized via selective intramolecular oxa-Michael addition from oleracone E. In addition, we investigated their possible lifespan-extension properties using Caenorhabditis elegans, which is excellently suited as an experimental model to study aging. A significant longevity effect was observed when nematodes were grown with 20 μM of oleracone E.

Stereoselective Tandem Synthesis of syn-1,3-Diol Derivatives by Integrating Olefin Cross-Metathesis, Hemiacetalization, and Intramolecular Oxa-Michael Addition.

Stereoselective tandem synthesis of syn-1,3-diol motifs, abundantly present in polyketide natural products and relevant pharmaceuticals, was achieved from homoallylic alcohols, α,β-unsaturated ketones, and aldehydes. Olefin cross-metathesis of homoallylic alcohols with α,β-unsaturated ketones, hemiacetalization of the resultant alcohols with aldehydes, and subsequent intramolecular oxa-Michael addition of the derived hemiacetals furnished syn-1,3-dioxane derivatives in good to excellent yields without isolation of any intermediates. The acetal moiety of the resultant syn-1,3-dioxanes could be cleaved chemoselectively/regioselectively under mild conditions in subsequent transformations.

Stereodivergent synthesis of cyclic γ-aminobutyric acid – GABA analogues

A novel synthetic route towards two series of enantiomerically pure cyclic analogues of 2,3-cis- and 2,3-trans-γ-aminobutyric acid (GABA) was developed. The route is based on the elongation and stereodivergent manipulation of a readily accessible enantiomerically pure γ-substituted α-aminolactone. The five-step route towards the 2,3-cis-substituted GABA analogues was achieved via straightforward carbon chain extension of the lactone using a non-classical Wittig reaction followed by chemoselective reduction and a protecting group switch. The five-step route towards the 2,3-trans-substituted GABA analogues employed elongation of the same aminolactone using a Horner-Wadsworth-Emmons reaction and highly stereoselective intramolecular oxa-Michael addition as the key synthetic manipulations. Altogether this chemistry has allowed the stereodivergent preparation of a novel class of GABA analogues in two diastereomeric series.

How an early or late transition state impacts the stereoselectivity of tetrahydropyran formation by intramolecular oxa-Michael addition.

The intramolecular oxa-Michael addition giving tetrahydropyrans has been examined experimentally using both acidic and basic catalysis. With acidic catalysis, the diequatorial product is exclusively obtained in a kinetically controlled reaction in all cases. Under basic conditions at low temperature, the reaction is again under kinetic control, but formation of the axial-equatorial isomer is generally favoured with an (E)-Michael acceptor, although isomerisation to the diequatorial isomer is observed at higher temperatures. Computationally, it is found that the acid catalysed reaction has a late transition state and the kinetic favouring of the diequatorial isomer has a steric explanation. In contrast, under strongly basic conditions, an early transition state is found. Electrostatic effects are likely to be the main contributor to the stereoselectivity for the (E)-isomer and steric interactions for the (Z)-isomer.

Total Synthesis of Complex Biosynthetic Late-Stage Intermediates and Bioconversion by a Tailoring Enzyme from Jerangolid Biosynthesis.

A highly convergent access to the late-stage biosynthetic intermediates projerangolid and jerangolid E is presented, and its utility is demonstrated by the synthesis of novel non-natural jerangolid derivatives. The key steps are fragment couplings by Julia-Kocienski olefination and olefin cross metathesis, as well as a stereoselective tetrahydropyran formation by intramolecular oxa-Michael addition. Bioconversion experiments with the tailoring O-methyltransferase JerF confirmed its proposed biosynthetic role and revealed relaxed substrate specificity of this enzyme as well as tolerance to organic cosolvents.

Mechanistic Insight into Asymmetric Hetero-Michael Addition of α,β-Unsaturated Carboxylic Acids Catalyzed by Multifunctional Thioureas.

Carboxylic acids and their corresponding carboxylate anions are generally utilized as Brønsted acids/bases and oxygen nucleophiles in organic synthesis. However, a few asymmetric reactions have used carboxylic acids as electrophiles. Although chiral thioureas bearing both arylboronic acid and tertiary amine were found to promote the aza-Michael addition of BnONH2 to α,β-unsaturated carboxylic acids with moderate to good enantioselectivities, the reaction mechanism remains to be clarified. Detailed investigation of the reaction using spectroscopic analysis and kinetic studies identified tetrahedral borate complexes, comprising two carboxylate anions, as reaction intermediates. We realized a dramatic improvement in product enantioselectivity with the addition of 1 equiv of benzoic acid. In this aza-Michael reaction, the boronic acid not only activates the carboxylate ligand as a Lewis acid, together with the thiourea NH-protons, but also functions as a Brønsted base through a benzoyloxy anion to activate the nucleophile. Moreover, molecular sieves were found to play an important role in generating the ternary borate complexes, which were crucial for obtaining high enantioselectivity as demonstrated by DFT calculations. We also designed a new thiourea catalyst for the intramolecular oxa-Michael addition to suppress another catalytic pathway via a binary borate complex using steric hindrance between the catalyst and substrate. Finally, to demonstrate the synthetic versatility of both hetero-Michael additions, we used them to accomplish the asymmetric synthesis of key intermediates in pharmaceutically important molecules, including sitagliptin and α-tocopherol.

Tetrahydronaphthalene as a precursor of new series of chalcones, flavanones, and flavone

An efficient synthetic route for a novel series of chalcones 2a-2d as well as for the corresponding flavanones 3a-3d and flavones 4a-4d, using functionalized tetrahydronaphthalene (THN), is described herein. The Claisen-Schmidt condensation of such THN and aromatic aldehydes, in the presence of an aqueous solution of KOH (40%), selectively gives the expected chalcones 2a-2d, which may further undergo an intramolecular oxa-Michael addition using piperidine, affording the corresponding flavanones 3a-3d in high yields. Alternatively, treatment of such chalcones 2a-2d with I$_{2}$/DMSO provides rapidly, in a one-pot oxidative cyclization, a series of flavones 4a-4d in excellent yields ranging from 85% to 90%.

The Furan Approach to the Synthesis of Natural Products having Highly Substituted Cyclic Ether Moieties

We describe the synthesis of useful building blocks towards the synthesis of many natural products bearing substituted cyclic ether moieties using our previously described method we called lsquo The Furan Approach rdquo and which is based on singlet oxygen oxidation of a furan ring followed by an intramolecular oxa Michael addition

Synthetic Approaches to 2,6-trans-Tetrahydropyrans

Being different from 2,6-cis-tetrahydropyrans (2,6-cis-THPs), the corresponding 2,6-trans-THPs are thermodynamically less stable and more challenging to construct. The fact that there are many natural products and/or bioactive molecules containing this 2,6-trans-THP subunit has led to the development of many efficient synthetic approaches to access 2,6-trans-THPs. This review summarizes various synthetic methods reported for this structural motif and/or related applications in the total synthesis of natural products.1 Introduction2 Nucleophilic Addition to an Oxocarbenium Ion (Strategy A)3 Intramolecular Oxa-Michael Addition (Strategy B)4 Intermolecular Michael Addition to Dihydropyranones (Strategy A)5 The Heck–Matsuda (Strategy A) Reaction and Oxa-Heck Cyclization (Strategy B)6 Intramolecular SN2 Substitution and Epoxide Opening (Strategy B)7 Miscellaneous Methods8 Conclusion and Outlook

Syntheses and Biological Activities of the LMNO, ent-LMNO, and NOPQR(S) Ring Systems of Maitotoxin.

Structure-activity relationship studies of maitotoxin (MTX), a marine natural product produced by an epiphytic dinoflagellate, were conducted using chemically synthesized model compounds corresponding to the partial structures of MTX. Both enantiomers of the LMNO ring system were synthesized via aldol reaction of the LM ring aldehyde and the NO ring ketone. These fragments were derived from a common cis-fused pyranopyran intermediate prepared through a sequence involving Nozaki-Hiyama-Kishi reaction, intramolecular oxa-Michael addition, and Pummerer rearrangement. The NOPQR(S) ring system, in which the original seven-membered S ring was substituted with a six-membered ring, was also synthesized through the coupling of the QR(S) ring alkyne and the NO ring aldehyde and the construction of the P ring via 1,4-reduction, dehydration, and hydroboration. The inhibitory activities of the synthetic specimens against MTX-induced Ca2+ influx were evaluated. The LMNO ring system and its enantiomer induced 36 and 18% inhibition, respectively, at 300 μM, whereas the NOPQR(S) ring system elicited no inhibitory activity.

Asymmetric synthesis of epohelmins A, B and 3-epi ent-epohelmin A

An efficient method for asymmetric synthesis of epohelmins A (3), B (4) and their isomer 24 is detailed in this report. The key feature in this divergent synthesis includes the SmI2-induced cross-coupling of N-tert-butanesulfinyl imine 10 with chiral aldehyde 9 derived from d-malic acid. A cascade cyclization to the pyrrolizidine skeleton is achieved in our synthetic route for epohelmins. In addition, an interesting intramolecular oxa-Michael addition was observed for epohelmin A (3).

Synthesis of Novel Fluorinated Benzofurans and Dihydrobenzofurans

Starting from easily accessible propargylic fluorides an intramolecular oxa-Michael addition affords, in good yields, new gem-difluo­rodihydrobenzofurans bearing an electrophilic double bond in position 2. On these intermediates nucleophilic additions and Diels–Alder reactions have been performed affording functionalized fluorinated dihydrobenzofurans. On the other hand, Pd-catalyzed defluorinations give the corresponding fluorine containing benzofurans.