Olefination Strategy Research Articles

Pd(ii)-catalyzed enantioselective C-H olefination and photoregulation of sterically hindered diarylethenes.

Sterically hindered diarylethenes with intrinsic chirality have shown great potential in chiral signal regulation, light-controlled liquid crystals (LCs), etc. Their unique enantiospecific phototransformation between axial chirality of ring-open isomers and central chirality of ring-closed isomers can break through the bottleneck of interference between multiple chiral centers in traditional chiral diarylethenes. However, these intrinsic chiral diarylethenes require necessary chiral resolution through preparative chiral HPLC, typically resulting in limited separation efficiency and production scale. Here, we present an enantioselective olefination strategy to directly construct intrinsic chiral diarylethenes from a prochiral sterically hindered diarylethene, achieving high yields and enantioselectivity. The resulting isomers can be further decorated by incorporating mesogenic units, and the derivatives enable the successful reversible photoregulation of blue, green, and red reflection colors of LCs with excellent thermal stability, fatigue resistance, and little texture disorderliness, demonstrating the practical application potential of direct enantioselective olefination in photoregulation with intrinsic chiral diarylethenes.

A Late-Stage Aryl C-H Olefination Strategy and Its Application Towards Global Proteome Profiling of ∆8-Tetrahydrocannabinol.

Drugs and bioactive natural products exert their pharmacological effects by engaging numerous cellular targets in our body. Identification of these protein targets is essential for understanding the mechanism-of-action of these compounds, thus contributing to improved drug design in drug discovery programs. Termed "in situ drug profiling", a common strategy for studying these bioactive compounds centralized on the covalent capture of protein targets along with a reporter tag to facilitate downstream proteomic analyses. Though highly successful, such a strategy required innate electrophilic traps to facilitate covalent capture, and its dependence on classical alkylation/acylation strategies to install reporter tags has restricted its applications on non-covalent compounds. Late-stage C-H functionalization (LSF) may resolve this by substituting biologically inert C-H bonds with desired electrophilic groups. Herein, we demonstrated this concept by arming a diverse range of electron-rich aromatic drugs and natural products with α,β-unsaturated esters, via late-stage C-H olefination with a arylthio-based carboxylic acid ligand developed by Ibanez and co-workers. We also showed that covalent probes generated from this LSF approach could be applied for "in situ drug profiling" of ∆8-THC, as exemplified by the successful target engagement of α-4db, a ∆8-THC-based probe, to its native target hCB2R. In combination with probe 7, a photoaffinity-based derivative of ∆8-THC, we identified several novel putative targets that could account for some of the effects in THC consumption. We anticipate our C-H LSF strategy to be widely adopted for future studies of non-covalent drugs.

Atroposelective Synthesis of Conjugated Diene-Based Axially Chiral Styrenes via Pd(II)-Catalyzed Thioether-Directed Alkenyl C-H Olefination.

The efficient stereoselective synthesis of conjugated dienes, especially those with axial chirality, remains a great challenge. Herein, we report the highly atroposelective synthesis of axially chiral styrenes with a conjugated 1,3-diene scaffold via a Pd(II)-catalyzed thioether-directed alkenyl C-H olefination strategy. This strategy features easy operation, mild reaction conditions, high functional group tolerance (69 examples), complete Z-selectivity, and excellent enantioselectivities (up to 99% ee). Notably, the highly enantioselective synthesis of atropisomers with two stereogenic axes were also achieved using this strategy (up to 99% ee and 97:3 dr). Moreover, the reaction could be scaled up, and the resulting axially chiral styrenes could be easily oxidized into chiral sulfoxide derivatives with high diastereoselectivities, which showed great promise as a new type of sulfur-olefin ligand.

Ruthenium-Catalyzed Directed C(3)–H Olefination of N-Acetyl-1,2-dihydroisoquinolines: A Method to Achieve C3-Olefinated Isoquinolines

A unique approach to achieve regioselective C(3)–H olefination of isoquinolines under ruthenium-catalyzed conditions has been developed. The acetyl group of N-acetyl-1,2-dihydroisoquinoline acts as a directing group for this C–H olefination strategy. Removal of the acetyl directing group by a simple method leads to a quick access to C-3 olefinated isoquinolines. The methodology is a very good alternative to the traditional Heck reaction and substrates with halogen substituents are very good candidates for the transformation.

A facile tandem double-dehydrative-double-Heck olefination strategy for pot-economic synthesis of (E)-distyrylbenzenes as multi-target-directed ligands against Alzheimer's disease employing C. elegans model

A concise, one pot and regioselective access to (E)-distyrylbenzenes (DSBs) from arylhalide and secondary phenylenediethanol, a stable precursor for in situ generation of divinylbenzene (DVB) to avoid its polymerization, is described for construction of double CC bond formation via tandem double-dehydrative-double-Heck (D-D-D-H) reaction using Palladium and ionic liquid [hmim]Br as a cooperative catalyst. It is noteworthy that this pot-economy approach also provides direct synthesis of hydroxylated distyrylbenzenes without requirement of protection-deprotection strategy. Importantly, the synthesized DSBs are tested for their protective activity against β amyloid reduction, acetylcholine esterase inhibition, lipid lowering and reactive oxygen species (ROS) reduction properties in transgenic Caenorhabditis elegans model wherein 1,3-bis((E)-4-(trifluoromethyl)styryl)benzene (5c) is found to be active across all above factors thus presenting lead molecule within multi-target-directed ligands (MTDLs) approach. Molecular docking studies were also performed to understand the interactions of potent DSBs with receptors.

ChemInform Abstract: Three‐Component Assembly of Conjugated Enyne Scaffolds via E‐Selective Olefination of Ynals.

AbstractUnder these conditions a number of conjugated enynes are available.

Three-Component Assembly of Conjugated Enyne Scaffolds via E-Selective Olefination of Ynals

Benefited by the accessible ynamido-lithium intermediates Ib from a Cu-catalyzed azide-alkyne cycloaddition in the presence of stoichiometric amounts of LiOH, a mild and flexible three-component route to conjugated enyne scaffolds was successfully achieved via a formal E-selective olefination strategy.

ChemInform Abstract: Access to Functionalized Steroid Side Chains via Modified Julia Olefination.

Various functionalized steroidal side chains were conveniently accessed by a modified Julia olefination strategy using a common sulfone donor and an appropriate α-branched aldehyde acceptor. For the coupling of these hindered classes of reaction partners (and in contrast to typically observed trends), the benzothiazolyl(BT)-sulfone anion gave superior outcomes compared to the phenyltetrazolyl(PT)-sulfone anion.

Access to Functionalized Steroid Side Chains via Modified Julia Olefination

Various functionalized steroidal side chains were conveniently accessed by a modified Julia olefination strategy using a common sulfone donor and an appropriate α-branched aldehyde acceptor. For the coupling of these hindered classes of reaction partners (and in contrast to typically observed trends), the benzothiazolyl(BT)-sulfone anion gave superior outcomes compared to the phenyltetrazolyl(PT)-sulfone anion.

Development of an Early Enabling Synthesis for PF-03052334-02: A Novel Hepatoselective HMG-CoA Reductase Inhibitor

Early process development work toward a promising pyrazole-based HMG-CoA reductase inhibitor is described. PF-03052334-02 (1) was prepared in 14 synthetic steps with a 21% overall yield, highlighted by a modified three-step hydroxypyrazole formation in which the yield was improved from 37% to 73%, a Suzuki/ozonolysis pathway that streamlined the downstream chemistry, and a reversed Wittig olefination strategy that improved the key coupling step from 50% to 95% yield. Multiple process hazards and most chromatography steps were removed, and a highly effective active pharmaceutical ingredient (API) salt formation, purification, and isolation protocol was also developed.

Making Mixtures to Solve Structures: Structural Elucidation via Combinatorial Synthesis

A domino Horner-Wadsworth-Emmons olefination strategy has been used to prepare homologous series of (polyen)ones, and through combinatorial elaboration, corresponding families of highly branched hydrocarbons. Gas chromatography-mass spectrometry of the mixtures has enabled the rapid and unambiguous identification of several highly branched alkanes of geochemical importance. This is the first example of the use of combinatorial synthesis for the elucidation of structural connectivity.

The Meyer–Schuster rearrangement for the synthesis of α,β-unsaturated carbonyl compounds

The Meyer-Schuster rearrangement is the conversion of propargyl alcohols into alpha,beta-unsaturated carbonyl compounds via a formal 1,3-hydroxyl shift and tautomerization. The major challenge associated with the Meyer-Schuster reaction is that of selectively promoting the desired rearrangement over the myriad other reaction pathways available to propargyl alcohols. This Perspective Article features recent advances in the Meyer-Schuster reaction, including several demonstrated techniques for improving the scope. Strengths and weaknesses of each technique are discussed, and outstanding problems that warrant further study are highlighted. The primary motivation for research and development of the Meyer-Schuster rearrangement is as a means of preparing alpha,beta-unsaturated carbonyl compounds as part of a two-stage olefination strategy.

Synthesis of Two Dipeptide Isosteres Containing Di- and Trisubstituted E-Configured Double Bonds

The stereoselective syntheses of a Tyr-Tyr and a Pro-Pro E-alkene isostere are described. While the Tyr-Tyr isostere was synthesized following a convergent olefination strategy, the trisubstituted E-configured double bond of the Pro-Pro isostere was generated by an Ireland-Claisen rearrangement. The configuration of all key intermediates containing new stereocenters was determined by X-ray crystallography.

Asymmetric Synthesis of 3‐Oxa‐15‐deoxy‐16‐(m‐tolyl)‐17,18,19,20‐tetranorisocarbacyclin and Its Neuroprotective Analogue 15‐Deoxy‐16‐(m‐tolyl)‐17,18,19,20‐tetranorisocarbacyclin Based on the Conjugate Addition–Azoalkene–Asymmetric Olefination Strategy

A fully stereocontrolled synthesis of 3-oxa-15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin (3-oxa-15-deoxy-TIC, 7 b) and a formal one of 15-deoxy-16-(m-tolyl)-17,18,19,20-tetranorisocarbacyclin (15-deoxy-TIC, 7 a) are described. 15-Deoxy-TIC is specific for the neuronal prostacyclin receptor (IP2) and exhibits neuroprotective activities, and the new 3-oxa-15-deoxy-TIC is expected to be metabolically more stable than 15-deoxy-TIC. The syntheses of 7 a and 7 b are based on the convergent conjugate addition-azoalkene-asymmetric olefination strategy. Key building blocks are the readily available bicyclic azoalkene 14 and the alkenylcopper derivative 15. The stereoselective conjugate addition of 15 to 14 gave hydrazone 13, which was stereoselectively converted to the bicyclic ketone 11. The key steps for the construction of the alpha side chain of 7 a and 7 b and the regioselective introduction of the endocyclic Delta6,6a double bond are: 1) a highly selective asymmetric olefination of ketone 11 with the chiral Horner-Wadsworth-Emmons reagent 28 and 2) a regioselective deconjugation of the alpha,beta-unsaturated ester (E)-10 with the chiral lithium amide 29, which gave the beta,gamma-unsaturated ester anti-9 with high selectivity. The homoallylic alcohol 8 served at a late stage as the joint intermediate in the syntheses of 7 a and 7 b. While an etherification of 8 furnished, after hydrolysis and deprotection, 3-oxa-15-deoxy-TIC, its alkylation afforded alcohol 37, the known precursor for the synthesis of 15-deoxy-TIC.

Olefination of Ketones Using a Gold(III)-Catalyzed Meyer−Schuster Rearrangement

An atom-economical and efficient olefination strategy for ketones is described. Ethoxyacetylide addition followed by a gold-catalyzed Meyer-Schuster rearrangement affords alpha,beta-unsaturated esters, generally in excellent overall yield from the starting ketones. The alkynophilicity of Au3+ promotes an interaction with the electron-rich acetylenes that catalyzes the Meyer-Schuster rearrangement selectively over other conceivable pathways.

Fully Stereocontrolled Syntheses of 3-Oxacarbacyclin and Carbacyclin by the Conjugate Addition-Azoalkene-Asymmetric Olefination Strategy

A fully stereocontrolled synthesis of 3-oxacarbacyclin (3) and a formal synthesis of carbacyclin (2) are described. The syntheses are based on the conjugate addition-azoalkene-asymmetric olefination strategy. Its key features are (1) the stereoselective establishment of the complete omega-side chain of 2 and 3 through conjugate addition of the enantiopure C13-C20 alkenylcopper derivative 10 to the enantiopure C6-C12 bicyclic azoalkene 9 and (2) the 5E-stereoselective construction of the alpha-side chain through a Horner-Wadsworth-Emmons olefination of the bicyclic ketone 7 with the chiral lithium phosphonoacetate 26 with formation of ester E-27. The allylic alcohol 6 serves at late stage as the joint intermediate in the synthesis of 2 and 3.

Hemi-synthesis and Biological Activity of New Analogues of Podophyllotoxin

Various 4-analogues of podophyllotoxin and epipodophyllotoxin were obtained via the formation of the corresponding 4-keto derivatives. Methyloximation of podophyllotoxone, followed by subsequent catalytic hydrogenation, gave stereoselective access to 4-α-amino-4-deoxypodophyllotoxin and from there, to the corresponding acetamido and formamido derivatives. Base-catalyzed isomerisation of 4-α-amino-4-deoxypodophyllotoxin led to the corresponding picropodophyllin isomer while the 4-β-amino afforded a neopodophyllotoxin-like derivative. On the other hand, oxirane and hydroxymethyl-containing analogues were prepared from podophyllotoxin and 4- epi-4′-demethyl-podophyllotoxin, using a Takai olefination strategy. In the latter series, carboxaldehyde- and carboxylic acid-containing derivatives were also synthesized.

Synthesis of new ethyl 9-methylene-13 E and 13 Z-retinoates via the Julia olefination reaction

Synthesis of new ethyl 9-methylene-13 E and 13 Z-retinoates via the 9-methylene C-15 sulphone 5 is reported. The Julia olefination strategy was used for building the C-20 skeleton.

ChemInform Abstract: Synthesis of Picropodophyllin Homolactone.

Abstract Based on a Wittig olefination strategy, the first synthesis of picropodophyllin homolactone 2 is described in nine steps and 30% overall yield from podophyllotoxine 1 . The relative configuration of 2 was unambiguously determined using 2D NOESY NMR and a Monte Carlo search protocol. This work corrects the literature on the synthesis of 2 .

Synthesis of picropodophyllin homolactone

Based on a Wittig olefination strategy, the first synthesis of picropodophyllin homolactone 2 is described in nine steps and 30% overall yield from podophyllotoxine 1. The relative configuration of 2 was unambiguously determined using 2D NOESY NMR and a Monte Carlo search protocol. This work corrects the literature on the synthesis of 2.