Stereoselective Olefin Research Articles

Bifunctional iron-catalyzed alkyne Z-selective hydroalkylation and tandem Z-E inversion via radical molding and flipping

The challenging synthesis of thermodynamic-unfavored cis-olefins through catalytic cross-coupling reactions requires the synergistic interaction of substrate-activating units and configuration-regulating catalysts. Successfully hitting these two birds with one stone, we herein develop a convenient photoredox access to Z-alkenes from alkynes and light alkanes with a bifunctional iron-catalyzed system possessing both C(sp3)−H activation and configuration-controlling abilities. The protocol exhibits 100% atom utilization, mild conditions, a broad substrate scope, and compatibility with multitudinous functional groups. The detailed reaction mechanism and the origin of geometry regulation are well investigated by experimental and computational studies. Progressively, a catalytic amount of diaryl disulfides is introduced for consecutive photoinduced Z−E isomerization via reversible radical addition and flipping. Big steric hindrance substituents assembled on the disulfide emerge necessity for suppressing double-bond migration. This tandem strategy paves a promising way for stereoselective alkene construction and will bring significant inspiration for the development of transition metal photocatalysis.

Co/Fe Dual Catalysis for Sequential Hydrosilylation–Isomerization: Access to Trisubstituted (E)‐Alkenyl Silanes from Terminal Alkynes

Comprehensive SummaryBy rational modification of electronic and steric properties of pincer ligands, a Co/Fe dual catalyst system is developed for one‐pot sequential Markovnikov alkyne hydrosilylation and stereoselective alkene isomerization. The protocol provides an atom‐economical and efficient approach to trisubstituted (E)‐alkenyl silanes from widely accessible terminal alkynes with high regio‐ and stereoselectivities under mild conditions. The utility of this reaction was demonstrated by gram‐scale synthesis and derivatization of bioactive molecules. The radical clock and trapping experiments indicated that radical pathway might be operative in the alkene isomerization step.

Carbene-mediated stereoselective olefination of vinyl sulfoxonium ylides with diazo compounds and acetals.

The development of stereoselective olefination using sulfur ylide-derived vinyl carbenes with diazo esters and acetals is reported. Both reactions proceed through nucleophilic addition to electrophiles at the γ-position of an in situ-generated 2-alkoxy furan intermediate. The synthetic utility of the developed method is demonstrated by the total synthesis of rubrolide E. Detailed mechanistic investigations and quantum chemical calculations provide insight into the reaction mechanism.

A Computational Evaluation of the Steric and Electronic Contributions in Stereoselective Olefin Polymerization with Pyridylamido-Type Catalysts.

A density functional theory (DFT) study combined with the steric maps of buried volume (%VBur) as molecular descriptors and an energy decomposition analysis through the ASM (activation strain model)-NEDA (natural energy decomposition analysis) approach were applied to investigate the origins of stereoselectivity for propene polymerization promoted by pyridylamido-type nonmetallocene systems. The relationships between the fine tuning of the ligand and the propene stereoregularity were rationalized (e.g., the metallacycle size, chemical nature of the bridge, and substituents at the ortho-position on the aniline moieties). The DFT calculations and %VBur steric maps reproduced the experimental trend: substituents on the bridge and on the ortho-positions of aniline fragments enhance the stereoselectivity. The ASM-NEDA analysis enabled the separation of the steric and electronic effects and revealed how subtle ligand modification may affect the stereoselectivity of the process.

Stereoselective Olefination with Sterically Demanding Julia-Kocienski Reagents: Total Synthesis of Oxo-prothracarcin, Oxo-tomaymycin, and Boseongazepine B.

Total syntheses of three pyrrolo[1,4]benzodiazepine anticancer antibiotic family members oxo-prothracarcin, oxo-tomaymycin, and boseongazepine B are described. The total syntheses feature late-stage stereoselective olefination employing modified Julia–Kocienski reagents that can be conveniently prepared in only two steps and allows for a significant reduction in the number of linear steps. Detailed density functional theory (DFT) studies explain the stereochemical outcome of the key step.

Structure units oriented approach towards collective synthesis of sarpagine-ajmaline-koumine type alkaloids

Sarpagine-Ajmaline-Koumine type monoterpenoid indole alkaloids represent a fascinating class of natural products with polycyclic and cage-like structures, interesting biological activities, and related biosynthetic origins. Herein we report a unified approach towards the asymmetric synthesis of these three types of alkaloids, leading to a collective synthesis of 14 natural alkaloids. Among them, akuammidine, 19-Z-akuammidine, vincamedine, vincarine, quebrachidine, vincamajine, alstiphylianine J, and dihydrokoumine are accomplished for the first time. Features of our synthesis are a new Mannich-type cyclization to construct the key indole-fused azabicyclo[3.3.1]nonane common intermediate, a SmI2 mediated coupling to fuse the aza-bridged E-ring, stereoselective olefinations to install either the 19-E or 19-Z terminal alkenes presented in the natural alkaloids, and an efficient iodo-induced cyclization to establish the two vicinal all-carbon quaternary centers in the Koumine-type alkaloids.

Secondary phosphine oxide-activated nickel catalysts for site-selective alkene isomerization and remote hydrophosphination

Catalytic systems that are readily modifiable to achieve olefin migration or remote functionalization are highly sought after in chemical synthesis. Here, we show that the combination of a commercially available nickel(II) pre-catalyst and a secondary phosphine oxide ligand enables site- and stereoselective alkene transposition for up to nine double-bond migrations within terminal and internal olefins under mild reductive conditions. Substrates bearing diverse functionalities including Brønsted acidic and reducible carbonyl groups are tolerated. Mechanistic and spectroscopic studies revealed the in situ generation of a catalytically active nickel-hydride species triggered by oxidative addition of the phosphine oxide. The reaction is amenable to regioconvergent isomerization as well as β-selective remote hydrophosphination when stoichiometric secondary phosphine oxide and base were employed.

Asymmetric synthesis and biological evaluation of (+)-cardiobutanolide, (−)-3-deoxycardiobutanolide and analogues as antiproliferative agents

Two natural products, (+)-cardiobutanolide and (−)-3-deoxycardiobutanolide, as well as five new analogues, were synthesized in several steps that included zinc-mediated THF ring opening, subsequent stereoselective olefination, and final Sharpless asymmetric dihydroxylation. In vitro antitumour activities of these compounds were evaluated against a panel of eight human tumour cell lines and one normal cell line. Some of compounds displayed powerful effects against tumour cells, but none of them were active toward normal cells. A SAR study revealed that the change of configuration at the C-6 and C-7 position of (+)-cardiobutanolide decreases antitumour activity of analogues. It also appears that the presence of a hydroxyl group at the C-3 position increases the activity of this type of lactones. A comparison of activities of conformationally rigid lactone goniofufurone with that of more flexible cardiobutanolide and 3-deoxycardiobutanolide indicates that steric flexibility has a positive effect on cytotoxicity. It was also confirmed that removal of the phenyl group may result in analogues of higher activity. Flow cytometry analysis revealed that the synthesized compounds did not induce apoptosis and necrosis of K562 cells. However, Western blot analysis showed that all compounds but one had an increased Bax/Bcl-2 protein expression ratio.

Continuous Flow Z‐Stereoselective Olefin Metathesis: Development and Applications in the Synthesis of Pheromones and Macrocyclic Odorant Molecules**

AbstractThe first continuous flow Z‐selective olefin metathesis process is reported. Key to realizing this process was the adequate choice of stereoselective catalysts combined with the design of an appropriate continuous reactor setup. The designed continuous process permits various self‐, cross‐ and macro‐ring‐closing‐metathesis reactions, delivering products in high selectivity and short residence times. This technique is exemplified by direct application to the preparation of a range of pheromones and macrocyclic odorant molecules and culminates in a telescoped Z‐selective cross‐metathesis/ Dieckmann cyclisation sequence to access (Z)‐Civetone, incorporating a serial array of continually stirred tank reactors.

Continuous Flow Z-Stereoselective Olefin Metathesis: Development and Applications in the Synthesis of Pheromones and Macrocyclic Odorant Molecules*.

The first continuous flow Z-selective olefin metathesis process is reported. Key to realizing this process was the adequate choice of stereoselective catalysts combined with the design of an appropriate continuous reactor setup. The designed continuous process permits various self-, cross- and macro-ring-closing-metathesis reactions, delivering products in high selectivity and short residence times. This technique is exemplified by direct application to the preparation of a range of pheromones and macrocyclic odorant molecules and culminates in a telescoped Z-selective cross-metathesis/ Dieckmann cyclisation sequence to access (Z)-Civetone, incorporating a serial array of continually stirred tank reactors.

Olefin Functionalization/Isomerization Enables Stereoselective Alkene Synthesis.

Despite tremendous efforts aimed at devising methods for stereoselective alkene synthesis, critical challenges are yet to be addressed. Direct access to a diverse range of 1aryl(boryl)-1-methyl-functionalized tri- and tetrasubstituted trans alkenes, entities that are prevalent in many important molecules of interest, through a catalytic manifold from readily available α-olefin substrates remains elusive. Here, we demonstrate that catalytic amounts of a nonprecious N-heterocyclic carbene-Ni(I) complex in conjunction with a sterically bulky base promote site- and trans-selective union of monosubstituted olefins with a wide array of electrophilic reagents to deliver tri- and tetrasubstituted alkenes in up to 92% yield and >98% regio- and stereoselectivity. The protocol is amenable to the preparation of carbon- and heteroatom-substituted C=C bonds, providing distinct advantages over existing transformations. Utility is highlighted through concise stereoselective synthesis of biologically active compounds.

Understanding the Mechanistic Requirements for Efficient and Stereoselective Alkene Epoxidation by a Cytochrome P450 Enzyme

The cytochrome P450 (CYP) family of heme monooxygenase enzymes commonly catalyzes enantioselective hydroxylation and epoxidation reactions. Epoxidation reactions have been hypothesized to proceed via multiple mechanisms involving different reactive intermediates. Here, we use activity, spectroscopic, structural, and molecular dynamics data to investigate the activity and stereoselectivity of 4-vinylbenzoic acid epoxidation by the bacterial enzyme CYP199A4 from Rhodopseudomonas palustris HaA2. The epoxidation of 4-vinylbenzoic acid by CYP199A4 proceeded with high enantioselectivity, giving the (S)-epoxide in 99% ee at an activity of 220 nmol nmol-CYP–1 min–1. Optical and EPR spectroscopy, redox potential measurements, and the crystal structure of 4-vinylbenzoic acid-bound CYP199A4 indicated the partial retention of an aqua ligand at the heme center in the presence of the substrate, providing a justification of the lower activity (∼20%) compared to the oxidative demethylation of 4-methoxybenzoic acid. Mutagenesis at the conserved acid–alcohol pair (D251/T252), which perturbs the generation of the reactive oxygen intermediates, was employed to investigate their role in epoxidation reactions. The T252A mutant increased the rate of turnover of the catalytic cycle, but an elevation in hydrogen peroxide generation via uncoupling resulted in a similar rate of epoxide formation. The activity of epoxidation significantly reduced with the D251N mutant. The chemoselectivity and stereoselectivity of the epoxidation reaction were maintained in the turnovers by these mutants. Overall, there was little evidence that other intermediates, aside from the archetypal reactive ferryl porphyrin cation radical, Compound I, contributed significantly to the epoxidation reaction. The observation of the high selectivity for the (S)-enantiomer was rationalized by molecular dynamics simulations. When the arrangement of the alkene and the active intermediate approached an ideal transition state structure for epoxidation, one face of the alkene was more often exposed to the iron oxo unit.

Regioselectivity and stereoselectivity of intramolecular [2 + 2] photocycloaddition catalyzed by chiral thioxanthone: a quantum chemical study.

Chiral photosensitizer-catalyzed stereoselective olefin cyclization has shown its significance in organic synthesis. In this work, we investigated the reaction mechanism, regioselectivity and stereoselectivity of photochemical intramolecular [2 + 2] cycloaddition reaction catalyzed by a chiral thioxanthone molecule using quantum chemical calculations. The reaction proceeded via an energy transfer from the triplet thioxanthone to the substrate, involving stepwise and sequential C-C bond formation. The first C-C bond formation was calculated to be the rate-limiting and selectivity-controlling step. The origin of stereoselectivity was found to be interaction-controlled by distortion/interaction analysis. In addition, the catalyst substituent effects (O vs. S vs. Se) on the stereoselectivity of the photocycloadditions were explored, which provides helpful mechanistic information for the design of related photoinduced reactions.

Intercepting fleeting cyclic allenes with asymmetric nickel catalysis.

Strained cyclic organic molecules, such as arynes, cyclic alkynes and cyclic allenes, have intrigued chemists for more than a century with their unusual structures and high chemical reactivity1. The considerable ring strain (30-50 kilocalories per mole)2,3 that characterizes these transient intermediates imparts high reactivity in many reactions, including cycloadditions and nucleophilic trappings, often generating structurally complex products4. Although strategies to control absolute stereochemistry in these reactions have been reported using stoichiometric chiral reagents5,6, catalytic asymmetricvariants to generate enantioenriched products have remained difficult to achieve. Here we report the interception of racemic cyclic allene intermediates in a catalytic asymmetric reaction and provide evidence for two distinct mechanisms that control absolute stereochemistry in such transformations: kinetic differentiation of allene enantiomers and desymmetrization of intermediate π-allylnickel complexes. Computational studies implicate a catalytic mechanism involving initial kinetic differentiation of the cyclic allene enantiomers through stereoselective olefin insertion, loss of the resultant stereochemical information, and subsequent introduction of absolute stereochemistry through desymmetrization of an intermediate π-allylnickel complex. These results reveal reactivity that is available to cyclic allenes beyond the traditional cycloadditions and nucleophilic trappings previously reported, thus expanding thetypes of product accessible from this class of intermediates. Additionally, our computational studies suggest two potential strategies for stereocontrol in reactions of cyclic allenes. Combined, these results lay the foundation for the development of catalytic asymmetric reactions involving these classically avoided strained intermediates.

Iridium-Catalyzed Stereoselective Alkene Isomerization

Iridium-Catalyzed Stereoselective Alkene Isomerization

Cobalt(II)-Catalyzed Stereoselective Olefin Isomerization: Facile Access to Acyclic Trisubstituted Alkenes.

Stereoselective synthesis of trisubstituted alkenes is a long-standing challenge in organic chemistry, due to the small energy differences between E and Z isomers of trisubstituted alkenes (compared with 1,2-disubstituted alkenes). Transition metal-catalyzed isomerization of 1,1-disubstituted alkenes can serve as an alternative approach to trisubstituted alkenes, but it remains underdeveloped owing to issues relating to reaction efficiency and stereoselectivity. Here we show that a novel cobalt catalyst can overcome these challenges to provide an efficient and stereoselective access to a broad range of trisubstituted alkenes. This protocol is compatible with both mono- and dienes and exhibits a good functional group tolerance and scalability. Moreover, it has proven to be a useful tool to construct organic luminophores and a deuterated trisubstituted alkene. A preliminary study of the mechanism suggests that a cobalt-hydride pathway is involved in the reaction. The high stereoselectivity of the reaction is attributed to both a π-π stacking effect and the steric hindrance between substrate and catalyst.

Breaking Symmetry Rules Enhance the Options for Stereoselective Propene Polymerization Catalysis

An example of breaking “Ewen’s symmetry rule” for olefin catalysis polymerization is proposed by DFT calculations. Catalyst precursors with Cs symmetry are suggested to promote the isotactic propene polymerization by a modification of the active site geometry obtained via coordination with AlH–alkyl species in solution. The origin of stereocontrol in olefin polymerization is due to a dual mechanism dictated by the chiral catalyst. These findings may expand the toolbox for promoting stereoselective olefin polymerization by transition metal catalysts.

Study and Applications of Stereoselective Olefin Metathesis Reactions

Study and Applications of Stereoselective Olefin Metathesis Reactions

Iron catalyzed stereoselective alkene synthesis: a sustainable pathway.

Replacing expensive or toxic transition metals with iron has become an important trend in transition metal catalyzed reactions. As an important part of this trend, the stereoselective construction of olefins under iron catalysis is an appealing and prolific research field. This article summarises the recent progress of a wide range of Fe-catalyzed reactions in accessing various stereodefined alkenes, including carbohalogenation, hydro/carbometalation of alkynes (allenes and dienes), alkylation and arylation of stereodefined (pseudo) haloalkenes or alkenyl metals, chelation-assisted C-H activation and other miscellaneous reactions.

Stereoselective Olefin Ring‐Opening Cross Metathesis Catalyzed by Molybdenum Imido Alkylidene N‐Heterocyclic Carbene Complexes

AbstractThe influence of the structure of cationic molybdenum imido alkylidene N‐heterocyclic carbene (NHC) catalysts, i. e. of [Mo(N‐2‐tert‐butyl‐C6H4) (CHCMe2Ph)(NHC)X+ B(ArF)4−] (NHC=1,3‐di(2‐Pr)imidazol‐2‐ylidene (iPr), 1,3‐dimesitylimidazol‐2‐ylidene (IMes); X=pyrrolide, OCH(CF3)2, B(ArF)4−=tetrakis(3,5‐bis(trifluoromethyl)phenyl)borate) and of [Mo(N‐3,5‐Me2‐C6H3)(CHCMe2Ph)(NHC)(CH3CN)X+ B(ArF)4−] (NHC=1,3‐dimesitylimidazol‐2‐ylidene, 1,3‐dimesitylimidazolin‐2‐ylidene (IMesH2); X=CF3SO3, OCPh(CF3)2) on E/Z‐selectivity in the ring‐opening cross‐metathesis (ROCM) of endo, endo‐2,3‐dicarbomethoxynorborn‐5‐ene (endo, endo‐DCMNBE), exo, exo‐2,3‐dicarbomethoxynorborn‐5‐ene (exo, exo‐DCMNBE), endo, exo‐2,3‐dicarbomethoxynorborn‐5‐ene ((+) DCMNBE) and 2,3‐exo,exo‐bis(acetoxymethyl)‐7‐oxabicyclo[2.2.l]hept‐5‐ene (7‐oxa‐NBE) with 1‐pentene, styrene, allyltrimethylsilane, allyl benzyl ether, allyl phenyl ether and allyl ethyl ether has been studied. With the exception of the ROCM reaction of endo, endo‐DCMNBE with styrene, all other ROCM reactions of endo, endo‐DCMNBE proceeded under thermodynamic control without any post‐metathesis isomerization reactions with full retention of the configuration of the newly formed 1,2‐disubstituted double bond as confirmed by kinetic studies. Similar accounts for selected homometathesis reactions. Catalyst structure‐selectivity correlations based on the buried volume, Vbur, of the N‐imido ligand are presented.magnified image