Disubstituted Alkenes Research Articles

Semisynthesis of Bis-Indole Alkaloid (-)-Melodinine K Enabled by a Combination of Biotransformation and Chemical Synthesis.

Enzymatic biotransformation has become a widely used technique in synthetic chemistry to achieve difficult chemical transformations. Cytochrome P450 monooxygenase enzymes found in nature carry out a wide range of difficult chemical reactions, such as the oxidation of the monoterpene indole alkaloid (-)-tabersonine at the unreactive 16th position on the indoline benzene ring in the biosynthesis of biologically active natural products such as the bis-indole alkaloid (-)-melodinine K. Herein, we describe the first semisynthesis of (-)-melodinine K enabled by a biological gram scale route to the northern fragment, (-)-16-hydroxytabersonine, as well as a chemical route to the southern fragment, (-)-pachysiphine, both derived from (-)-tabersonine and subsequently coupled in only eight linear steps. (-)-16-Hydroxytabersonine is produced through an enzymatic biotransformation with a genetically modified Saccharomyces cerevisiae yeast strain expressing a tabersonine 16-hydroxylase enzymeto enable regioselective oxidation on multigram scale, and (-)-pachysiphine is produced through stereoselective and regioselective epoxidation of the disubstituted alkene.

A base-controlled switch of SO2 reincorporation in photocatalyzed radical difunctionalization of alkenes

A base-controlled switch of SO2 reincorporation in photocatalyzed radical difunctionalization of alkenes

Total Synthesis of Skipped Diene Natural Products

AbstractSkipped dienes (1,4‐dienes) are widely distributed in a variety of biologically active natural products. The synthesis of these skipped dienes is a relatively undeveloped area compared with that of conjugated dienes (1,3‐dienes) due to the sp3‐hybridized carbon between two olefins. Especially, development of methods to meet both high stereoselectivity and convergency is highly challenging. This review focuses on recent advances in the synthesis of skipped dienes in the total synthesis of complex natural products, which are classified into three classes; a) skipped dienes comprised of two disubstituted olefins, b) skipped dienes including trisubstituted olefin(s), and c) 3‐methyl skipped dienes.

Synthesis of an allylic gem-difluoromethylene building block via radical-mediated difluorocyclopropane ring opening

We report an optimised and highly efficient synthetic route towards a valuable functionalised fluorinated building block. The key-steps include difluorocyclopropanation of a disubstituted alkene with a suitable difluorocarbene precursor, and a radical-induced cyclopropane ring-opening, operating via an iodide atom transfer reaction.

Transition Metal (Ni, Cu, Pd)-Catalyzed Alkene Dicarbofunctionalization Reactions.

Recently, alkene dicarbofunctionalization, i.e., the powerful organic synthesis method of alkene difunctionalization with two carbon sources, emerged as a formidable reaction with immense promise to synthesize complex molecules expeditiously from simple chemicals. This reaction is generally achieved with transition metals (TMs) through interception by carbon sources of an alkylmetal [β-H-C(sp3)-[M]] species, a key intermediate prone to undergo rapid β-H elimination. Related prior reports, since Paolo Chiusoli and Catellani's work in 1982 [ Tetrahedron Lett. 1982, 23, 4517], have used bicyclic and disubstituted terminal alkenes, wherein β-H elimination is avoided by geometric restriction or complete lack of β-H's. With reasoning that β-H-C(sp3)-[M] intermediates could be rendered amenable to interception with the use of first row late TMs and formation of coordination-assisted transient metallacycles, these two strategies were implemented to address the β-H elimination problem in alkene dicarbofunctionalization reactions.Because first row late TMs catalyze C(sp3)-C(sp3) coupling, Cu and Ni were anticipated to impart sufficient stability to β-H-C(sp3)-[M] intermediates, generated catalytically upon alkene carbometalation, for their subsequent interception by carbon electrophiles/nucleophiles in three-component reactions. Additionally, such an innate property could enable alkene difunctionalization with carbon coupling partners through entropically driven cyclization/coupling reactions. The cyclometalation concept to stabilize intractable β-H-C(sp3)-[M] intermediates was hypothesized when three-component reactions were performed. The idea of cyclometalation to curtail β-H elimination is founded upon Whitesides's [ J. Am. Chem. Soc. 1976, 98, 6521] observation that metallacycles undergo β-H elimination much slower than acyclic alkylmetals.In this Account, examples of alkene dicarbofunctionalization reactions demonstrate that Cu and Ni catalysts could enable cyclization/coupling of alkenylzinc reagents, alkyl halides, and aryl halides to afford complex carbo- and heterocycles. In addition, forming coordination-assisted transient nickellacycles enabled regioselective performance of three-component dicarbofunctionalization of various alkenyl compounds. In situ reaction of [M]-H with alkenes generated after β-H elimination induced an unprecedented metallacycle contraction process, in which six-membered metal-containing rings shrank to five-membered cycles, allowing creation of new carbon-carbon bonds at allylic (1,3) positions. Applications of these regioselective alkene dicarbofunctionalization reactions are discussed.

Experimental and theoretical investigation of the reaction of a 3-amidothiophene derivative with various carbonyl compounds.

The reactions of a 3-amidothiophene derivative, which is a partial structure of penthiopyrad, with various carbonyl compounds were investigated. Depending on the carbonyl compound that was used as a reactant, different products (alkenes and bis-products) were obtained from the attack of the carbon at the 2-position of the 3-amidothiophene on the carbonyl compounds. Density functional theory (DFT) calculations revealed that dehydration conditions were important for the first carbonyl addition to shift the reaction toward the product, as the products are more unstable than reactants other than aldehyde. The DFT calculations also suggested that the relative stability of the alkenyl state determined whether the second bis-product formation would proceed; i.e., the relatively unstable disubstituted alkene led to bis-products, and the stable trisubstituted or conjugated alkene yielded alkenyl products.

Total Synthesis of Viridiofungins A and B.

The total synthesis of viridiofungins A (1) and B (2) via β-lactone 3 in 13 steps is reported. Key steps included an HF-mediated rearrangement of cyclobutene diester 9 to form a bicyclic lactone 6, an olefin cross metathesis between disubstituted alkene 3 and alkene 4 in which isomerization was suppressed, and a novel β-lactone ring opening to form the amide. Deprotection then gave either viridiofungin A (1) or B (2) in high yield.

Indene Derived Phosphorus‐Thioether Ligands for the Ir‐Catalyzed Asymmetric Hydrogenation of Olefins with Diverse Substitution Patterns and Different Functional Groups

AbstractA family of phosphite/phosphinite‐thioether ligands have been tested in the Ir‐catalyzed asymmetric hydrogenation of a range of olefins (50 substrates in total). The presented ligands are synthesized in three steps from cheap indene and they are air‐stable solids. Their modular architecture has been crucial to maximize the catalytic performance for each type of substrate. Improving most Ir‐catalysts reported so far, this ligand family presents a broader substrate scope, covering different substitution patterns with different functional groups, ranging from unfunctionalized olefins, through olefins with poorly coordinative groups, to olefins with coordinative functional groups. α,β‐Unsaturated acyclic and cyclic esters, ketones and amides were hydrogenated in enantioselectivities ranging from 83 to 99% ee. Enantioselectivities ranging from 91 to 98% ee were also achieved for challenging substrates such as unfunctionalized 1,1′‐disubstituted olefins, functionalized tri‐ and 1,1′‐disubstituted vinyl phosphonates, and β‐cyclic enamides. The catalytic performance of the Ir‐ligand assemblies was maintained when the environmentally benign 1,2‐propylene carbonate was used as solvent.magnified image

A computational study of the reaction mechanism of 2,2-azobis(isobutyronitrile)-initiated oxidative cleavage of geminal alkenes.

A computational study of 2,2-azobis(isobutyronitrile) (AIBN)-initiated aerobic oxidative cleavage of alkenes is carried out employing density functional theory (DFT) and high-level coupled-cluster methods, such as coupled-cluster singles and doubles with perturbative triples [CCSD(T)]. Our computations show that the barriers for the formation of dioxetane derivatives suggested by Xu and co-workers (J. Org. Chem., 2014, 79, 7220-7225) for the reaction mechanism of aerobic oxidative cleavage of alkenes are computed to be higher than 65 kcal mol-1. This barrier is relatively high under the reaction conditions. Our results for the Xu mechanism indicate that the reaction does not proceed via the formation of a dioxetane ring under the reaction conditions. Our results demonstrate that the reaction of aerobic oxidative cleavage of geminal alkenes in the presence of AIBN is initiated by the peroxyl radical 9, contrary to the isobutyronitrile radical 2. Our results show that the 2-(2-hydroxyl-1,1-diarylethoxy)-2-methylpropanenitrile radical (15) does not appear throughout the reaction scheme and the reaction progresses over the 2-(2-hydroxyl-2,2-diarylethoxy)-2-methylpropanenitrile radical (13) rather than the 2-(2-hydroxyl-1,1-diarylethoxy)-2-methylpropanenitrile radical (15). Our results are in agreement with the experimental results for the aerobic oxidative cleavage of the geminal disubstituted alkenes. Our results also demonstrate that the epoxide derivatives can be formed as an intermediate under the reaction conditions. This reaction is not applicable for pyridine derivatives due to the conversion of vinylpyridine derivatives to N-oxide derivatives.

Pd-Catalyzed Domino Imidoylation/Heck/C(sp2)-H Cyclization: Isocyanide Relay Strategy toward Tricyclic-Fused Heterocycles Containing an All-Carbon Quaternary Center.

A palladium-catalyzed domino process for the quick assembly of tricyclic-fused heterocycles starting from aryl iodides and functionalized isocyanides containing a disubstituted terminal alkene has been developed. The process is triggered by intermolecular isocyanide insertion, followed by Heck-type carbopalladation of the intramolecular alkene moiety and subsequent C(sp2)-H activation. Moreover, an asymmetric version of this reaction could also be realized in good yield with moderate enantioselectivity after preliminary exploration of chiral ligands.

Iron-Catalyzed Tunable and Site-Selective Olefin Transposition.

The catalytic isomerization of C-C double bonds is an indispensable chemical transformation used to deliver higher-value analogues and has important utility in the chemical industry. Notwithstanding the advances reported in this field, there is compelling demand for a general catalytic solution that enables precise control of the C═C bond migration position, in both cyclic and acyclic systems, to furnish disubstituted and trisubstituted alkenes. Here, we show that catalytic amounts of an appropriate earth-abundant iron-based complex, a base and a boryl compound, promote efficient and controllable alkene transposition. Mechanistic investigations reveal that these processes likely involve in situ formation of an iron-hydride species which promotes olefin isomerization through sequential olefin insertion/β-hydride elimination. Through this strategy, regiodivergent access to different products from one substrate can be facilitated, isomeric olefin mixtures commonly found in petroleum-derived feedstock can be transformed to a single alkene product, and unsaturated moieties embedded within linear and heterocyclic biologically active entities can be obtained.

Stereoselective Oxidative Rearrangement of Disubstituted Unactivated Alkenes Using Hypervalent Iodine(III) Reagent.

The stereoselective oxidative rearrangement of disubstituted unactivated olefins has been achieved using a hypervalent iodine(III) reagent. The aryl group undergoes 1,2-migration to give tert-α-arylated aldehydes (as acetals). The preparation of these aldehydes/acetals, especially containing a tert-benzylic stereocenter, has remained challenging. This migration-based method provides a complementary approach over the known α-substitution-based methods for accessing this class of molecules.

A site-selective amination catalyst discriminates between nearly identical C-H bonds of unsymmetrical disubstituted alkenes.

C–H activation reactions enable chemists to unveil new retrosynthetic disconnections and streamline conventional synthetic approaches. A longstanding challenge in C–H activation is the inability to distinguish electronically and sterically similar C–H bonds. Although numerous synergistic combinations of transition-metal complexes and chelating directing groups have been utilized to distinguish C–H bonds, undirected regioselective C–H functionalization strategies remain elusive. Herein, we report a regioselective C–H activation/amination reaction of various unsymmetrical dialkyl-substituted alkenes. The regioselectivity of C–H activation is correlated to the electronic properties of allylic C–H bonds indicated by the corresponding 1JCH coupling constants. A linear relationship between the difference of 1JCH coupling constants of the two competing allylic C–H bonds (Δ1JCH) and the C–H activation barriers (ΔΔG‡) has also been determined.

Palladium-Catalyzed Insertion of Ethylene and 1,1-Disubstituted Difunctional Olefins: An Experimental and Computational Study.

Insertion or coordination copolymerization of ethylene with di-substituted olefins is challenging and the choice of di-substituted mono-functional olefin versus di-substituted di-functional olefin (DDO) appears to be decisive. Here we show that DDO-inserted species are amenable to ethylene insertion and polymerization. DDOs such as 2-acetamidoacrylic acid (AAA), methyl 2-acetamidoacrylate (MAAA), and ethyl 2-cyanoacrylate (ECA) were treated with palladium complex [{P∧O}PdMe(L)] (P∧O=κ2 -P,O-Ar2 PC6 H4 SO2 O with Ar=2-MeOC6 H4 ; L=C2 H6 OS) and the existence of respective insertion intermediates in moderate yield (up to 37 %) was established. These intermediates were exposed to ethylene and corresponding ethylene-inserted products were isolated and characterized. A careful comparison with three model compounds confirmed ethylene insertion and polymerization. Thus, the combined experimental and computational investigations show that DDO-inserted species can undergo ethylene insertion and polymerization.

Iridium(I)-Catalyzed α-C(sp3)-H Alkylation of Saturated Azacycles.

Saturated azacycles are commonly encountered in bioactive compounds and approved therapeutic agents. The development of methods for functionalization of the α-methylene C-H bonds of these highly privileged building blocks is of great importance, especially in drug discovery. While much effort has been dedicated toward this goal by using a directed C-H activation approach, the development of directing groups that are both general as well as practical remains a significant challenge. Herein, the design and development of novel amidoxime directing groups is described for Ir(I)-catalyzed α-C(sp3)-H alkylation of saturated azacycles using readily available olefins as coupling partners. This protocol extends the scope of saturated azacycles to piperidines, azepane, and tetrahydroisoquinoline that are incompatible with our previously reported directing group. A variety of olefin coupling partners, including previously unreactive disubstituted terminal olefins and internal olefins, are compatible with this transformation. The selectivity for a branched α-C(sp3)-alkylation product is also observed for the first time when acrylate is used as the reaction partner. The development of practical, one-step installation and removal protocols further adds to the utility of amidoxime directing groups.

Controlling reactivity in the Fujiwara–Moritani reaction: Examining solvent effects and the addition of 1,3-dicarbonyl ligands on the oxidative coupling of electron rich arenes and acrylates

A palladium-catalysed direct alkenation of electron rich arenes in the presence of K2S2O8 with an acetic acid/1,4-dioxane solvent combination has been developed. The 1,4-dioxane co-solvent dramatically influences the rate of reaction, giving selectively disubstituted alkenes, while the addition of acetylacetone ligands was shown to increase site selectivity for the alkenation of monofunctionalized arenes. The participation of these carbonyl ligands has been confirmed by ESI-MS studies, with some key in situ intermediates in the catalytic cycle identified. A variety of electron rich arenes and olefinic substrates can be utilised in the direct oxidative coupling to give disubstituted alkenes in moderate to good yields.

Synthesis of Unsaturated Silyl Heterocycles via an Intramolecular Silyl-Heck Reaction.

We report the synthesis of unsaturated silacycles via an intramolecular silyl-Heck reaction. Using palladium catalysis, silicon electrophiles tethered to alkenes cyclize to form 5- and 6-membered silicon heterocycles. The effects of alkene substitution and tether length on the efficiency and regioselectivity of the cyclizations are described. Finally, through the use of an intramolecular tether, the first examples of disubstituted alkenes in silyl-Heck reactions are reported.

Calcium-Catalyzed Formal [5 + 2] Cycloadditions of Alkylidene β-Ketoesters with Olefins: Chemodivergent Synthesis of Highly Functionalized Cyclohepta[b]indole Derivatives.

The calcium-catalyzed, formal [5 + 2] cycloaddition of indolyl alkylidene β-ketoesters with mono- and disubstituted aryl olefins to form cyclohepta[b]indole derivatives has been established. Unanticipated chemodivergence with phenyl vinyl sulfide/ether revealed a double [5 + 2] cycloaddition cascade providing ethano-bridged cyclohepta[b]indoles. Overall, the method's highlights include: (1) use of a green, calcium-based catalyst (2.5 mol % loading); (2) reaction times under 1 h; (3) mild reaction conditions; (4) substrate-derived chemodivergence; (5) functional group tolerance; and (6) examples of derivatization.

Copper-Catalyzed [4+2] Cycloaddition of 9 H-Cyclohepta[ b]pyridine-9-one and Electron-Rich Alkenes.

9 H-Cyclohepta[ b]pyridin-9-one was used as a diene cycloaddition partner to construct [3.2.2] bicycles in a copper-catalyzed [4+2] cycloaddition. Oxygen- and nitrogen-substituted terminal, disubstituted, trisubstituted, and cyclic alkenes reacted to afford the cycloadducts as single constitutional isomers in 48-80% yields and diastereomeric ratios up to 5.6:1.

Enantioselective C2-Alkylation of Indoles through a Redox-Relay Heck Reaction of 2-Indole Triflates.

A palladium-catalyzed enantioselective redox-relay Heck reaction of 2-indole triflates and disubstituted alkenes is reported. This process combines readily available indole triflates with a variety of alkenes to afford a range of indole derivatives bearing a stereocenter adjacent to C2. Enantioselectivity is achieved through use of a simple pyridine-oxazoline ligand. Tuning the electronics of the indole, through judicious choice of N-protecting group, is required to ensure selective β-hydride elimination away from the indole core. Utility of this method is highlighted in a modular formal synthesis of an S1P1 agonist precursor developed by Merck.