- Total syntheses and structure-activity relationship study of parthenolide analogues
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Two new parthenolide analogues were obtained by total synthesis and assayed for their in vitro anticancer activities to study their structure-activity relationship. Based on the structure and anticancer activity results, two new SAR can be drawn: (1) replacement of the lactone moiety with lactam moiety greatly decreased the anticancer activity; (2) the C-14 methyl group of parthenolide might be important for its high anticancer activity.
- Long, Jing,Ding, Ya-Hui,Wang, Pan-Pan,Zhang, Quan,Chen, Yue
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- Total Synthesis of Amphirionin-4
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An expeditious enantioselective total synthesis of amphirionin-4, a remarkably potent promoter of the proliferation of ST-2 cells, has been achieved from (±)-(E)-1,4-hexadien-3-ol by an 8-pot sequence that features the Sharpless kinetic resolution, iodoetherification, and the CBS reduction to install the stereocenters, utilization of four one-pot transformations to streamline the synthetic process, and the Stille coupling reaction at nearly the center of the target molecule to complete the total synthesis.
- Ogura, Yusuke,Sato, Hikaru,Kuwahara, Shigefumi
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- Synthesis of crossed [2 + 2] photocycloadducts: a novel approach to the synthesis of bridged bicyclic alkenes.
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[reaction: see text] A solution to the synthesis of "crossed" intramolecular [2 + 2] photocycloadducts has been achieved. Through the use of a temporary heteroatom linker, the equivalent of a crossed photocycloadduct can be accessed at the expensive of the normal "straight" adduct. Selectivity as high as 94:6 for the "crossed" adduct has been observed.
- Crimmins,Hauser
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- Direct observation of the molecular structural changes during the claisen rearrangement including the transition state
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The detailed processes in the Claisen rearrangement were observed. The process was vibrationally excited in the electronic ground state by a stimulated Raman process using a 5-fs pulse. The Claisen rearrangement was found to follow a three-step pathway. At first, the C4-O bond is weakened to generate a bisallyl-like intermediate. Next, the formation of a weak C 1-C6 bond results in the generation of an aromatic-like intermediate. Finally, C4-O breaking and C1-C6 formation occur simultaneously to generate the product.
- Iwakura, Izumi,Yabushita, Atushi,Kobayashi, Takayoshi
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- Improved synthetic route to enantiomerically pure samples of the tetrahydropyran-2-ylacetic acid core associated with the phytotoxic polyketide herboxidiene
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The phosphine oxide (2), which embodies the tetrahydropyran-2-ylacetic acid core associated with the phytotoxic polyketide herboxidiene (1) and which is a key intermediate in a projected synthesis of this natural product, has been prepared in a highly enantio- and diastereo-selective manner. The pivotal steps in this new and improved synthesis of compound (2) involve Katsuki-Sharpless asymmetric epoxidation of the allylic alcohol (4) to give epoxide (7) and subsequent ring-cleavage of the latter compound with trimethylaluminium to give diol (9). The derived acetate (10) is then readily ozonolysed to give the previously reported aldehyde (11), although now in high enantiomeric excess. Compound (11) can be elaborated, by established chemistry, to the target oxide (2). CSIRO 2000.
- Barnwell, Martin G.,McLeod, Malcolm D.,Premraj, Rajaratnam,Simpson, Gregory W.
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- Asymmetric synthesis of the main core of kaurane family members triggered by an oxidative polycyclization-pinacol tandem process
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Polycyclization processes represent expeditious routes used in both nature and the laboratory to produce complex polycyclic molecules. A new stereoselective oxidative variant of such a polycyclization has been developed in which the cascade is triggered by a phenol dearomatization and is concluded by a pinacol transposition. This unprecedented avenue combines the synthetic power of a polycyclization and a transposition in tandem and enables the rapid formation of the tetracyclic main core of kaurane diterpenes containing several asymmetric and quaternary carbon centers in a single step from a simple phenol derivative.
- Desjardins, Samuel,Maertens, Ga?tan,Canesi, Sylvain
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- New entry to the Pauson-Khand reaction: Trimethylgermyl group at the triple bond terminus as a latent functional group
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The Pauson-Khand reaction of enynes possessing a trimethylgermyl group at the alkyne terminus afforded the corresponding bicyclo[3.3.0]octenone and bicyclo[4.3.0]nonenone skeletons in a stereoselective manner. The resulting trimethylgermyl group of the bicyclic compounds was then converted to the iodo group, which was used for further elaboration. Thus, the trimethylgermyl group at the triple bond terminus was shown to be a precursor for other appendages.
- Mukai, Chisato,Kozaka, Takashi,Suzuki, Yukihiro,Kim, In Jong
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- Towards novel difluorinated sugar mimetics; syntheses and conformational analyses of highly-functionalised difluorinated cyclooctenones
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Highly-functionalised difluorinated cyclooctenones were synthesised from trifluoroethanol using either metallated difluoroenol acetal or carbamate chemistry, followed by a [2,3]-Wittig rearrangement or aldol reaction. Efficient RCM reactions afforded the title compounds which showed rather restricted fluxional behaviour by VT 19F NMR. Topological characterisation by molecular modelling and NOESY/ROESY experiments offered a number of challenges, but allowed the identification of two favoured boat-chair conformers which interconverted by pseudorotation with relatively large activation barriers. The Royal Society of Chemistry 2005.
- Griffith, Gerry A.,Percy, Jonathan M.,Pintat, Stephane,Smith, Clive A.,Spencer, Neil,Uneyama, Emi
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- Magnetic and spin effects in photolysis of aqueous solutions of cyclopentanone
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Chemical nuclear polarization in photolysis of aqueous solutions of cyclopentanone has been studied. The products of the photolysis of liquid and frozen solutions have been determined. Kinetic investigations were carried out at different temperatures. The influence of an external magnetic field (0.37 T) and of a gradient magnetic field produced by barium hexaferrite and Nd 15Fe62.5B5.5Co16Al1 plates has been revealed. The mechanisms underlying the appearance of magnetic and spin effects are discussed.
- Skakovskii,Ogorodnikova,Tychinskaya,Murashko,Kozlov,Rykov
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- Intramolecular diels-alder reactions of siloxacyclopentene constrained trienes
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The synthesis of siloxacyclopentene-constrained trienes 7 and 10 and studies of their IMDA cycloadditions are described. The use of appropriately chosen thermal or Lewis acid conditions allows for cycloadducts 3-6 to be obtained with high levels of diastereoselectivity. These adducts possess frans-relationships between the hydroxyl group and the adjacent ring fusion proton, a stereochemical relationship not previously attainable in IMDA reactions.
- Halvorsen, Geoff T.,Roush, William R.
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- Selective hydroformylation of open-chain conjugated dienes promoted by mesitylene-solvated rhodium atoms to give β,γ unsaturated monoaldehydes
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The hydroformylation of 1,3-butadiene, 2-methyl-1,3-butadiene and 1,3-pentadiene using rhodium vapour-mesitylene cocondesates as a catalytic precursor is reported.The reaction gives β,γ-unsaturated monoaldehydes with high chemoselectivity and regioselectivity. η3-Butenyl complexes, derived from the addition of Rh-H species to the conjugated double-bound system, are likely to be intermediates, as suggested by deuterioformylation experiments. Keywords: Rhodium vapour; Hydroformylation; Conjugated dienes; Catalysis; Unsaturated aldehydes
- Bertozzi, Sergio,Campigli, Nedo,Vitulli, Giovanni,Lazzaroni, Raffaello,Salvadori, Piero
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- Thermal rearrangement of allyl vinyl ether: Heavy-atom kinetic isotope effects and the transition structure
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Kinetic isotope effects (KIE) in the rearrangement of allyl vinyl ether (1, 3-oxa-1,5-hexadiene) to 4-pentenal (2) were measured for labeling with 14C at the 2-, 4-, and 6-positions and with 18O at the 3-position. BEBOVIB modeling calculations were applied successfully to the heavy-atom KIE and previously reported KIE for deuterium substitution at positions 4 and 6. From the calculations, it is deduced that the C4-O bond is 50-70% broken and the C1-C6 bond 10-30% formed in the transition structure. Further, there is strong coupling between the allyl and vinyloxy fragments, strong bonding within the allyl but relatively weak bonding within the vinyloxy fragment.
- Kupczyk-Subotkowska, Lidia,Saunders Jr., William H.,Shine, Henry J.,Subotkowski, Witold
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- Gold(I)-catalyzed intramolecular [4+3]-cycloaddition reactions with furan propargyl esters as the substrates: Carbenoid vsstabilized allyl cation
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The tricyclic ring system with an oxabicyclo[3.2.1]octadiene and a fused six-membered ring was produced efficiently using the readily available propargyl ester furan substrate in the presence of a Au(I) complex. The reaction involves a tandem 3,3-rearrangement of the propargyl ester followed by an intramolecular [4+3]-cycloaddition reaction. Both the primary ligand of the gold complex (N-heterocyclic carbene; NHC) and a neutral dynamic ligand (PhCN) are important for the success of the reaction. Georg Thieme Verlag Stuttgart. New York.
- Gung, Benjamin W.,Conyers, Ryan C.,Wonser, Josh
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- SINDO1 STUDY OF PHOTOISOMERIZATION AND PHOTOFRAGMENTATION OF CYCLOPENTANONE.
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The photoisomerization of cyclopentanone to 4-pentenal and the photofragmentation to cyclobutane and carbon monoxide or to two ethylene and carbon monoxide was investigated by the SINDO1 method including configuration interaction (CI). Structures and energies of all pertinent ground and excited states as well as transition states and intermediates were calculated. The mechanism for all reactions involves excitation to S//1 and intersystem crossing to T//1 or T//2. The triplets lead to diradical intermediates from which further reaction to the products takes place. The dependence of product distribution on excitation wavelength is discussed.
- Mueller-Remmers,Mishra,Jug
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- Photoinduced Palladium-Catalyzed Dicarbofunctionalization of Terminal Alkynes
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Herein, a conceptually distinct approach was developed that allowed for the dicarbofunctionalization of alkynes at room temperature using simple, bench-stable alkyl iodides and a second molecule of alkyne as coupling partner. Specifically, the photochemical activation of palladium complexes enabled this strategic dicarbofunctionalization via addition of alkyl radicals from secondary and tertiary alkyl iodides and formation of an intermediate palladium vinyl complex that could undergo subsequent Sonogashira reaction with a second alkyne molecule. This alkylation–alkynylation sequence allowed the one-step synthesis of 1,3-enynes including heteroarenes and biologically active compounds with high efficiency without exogenous photosensitizers or oxidants and now opens up pathways towards cascade reactions via photochemical palladium catalysis.
- Yang, Zhen,Koenigs, Rene M.
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supporting information
p. 3694 - 3699
(2021/02/01)
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- Backbone-Photodegradable Polymers by Incorporating Acylsilane Monomers via Ring-Opening Metathesis Polymerization
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Materials capable of degradation upon exposure to light hold promise in a diverse range of applications including biomedical devices and smart coatings. Despite the rapid access to macromolecules with diverse compositions and architectures enabled by ring-opening metathesis polymerization (ROMP), a general strategy to introduce facile photodegradability into these polymers is lacking. Here, we report copolymers synthesized via ROMP that can be degraded by cleaving the backbone in both solution and solid states under irradiation with a 52 W, 390 nm Kessil LED to generate heterotelechelic low-molecular-weight fragments. To the best of our knowledge, this work represents the first instance of the incorporation of acylsilanes into a polymer backbone. Mechanistic investigation of the degradation process supports the intermediacy of an α-siloxy carbene, formed via a 1,2-photo Brook rearrangement, which undergoes insertion into water followed by cleavage of the resulting hemiacetal.
- Huang, Banruo,Qian, Yiwen,Toste, F. Dean,Vargo, Emma,Wei, Mufeng,Xu, Ting
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supporting information
p. 17920 - 17925
(2021/11/12)
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- A Modular and Diastereoselective 5 + 1 Cyclization Approach to N-(Hetero)Aryl Piperidines
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A new general de novo synthesis of pharmaceutically important N-(hetero)aryl piperidines is reported. This protocol uses a robustly diastereoselective reductive amination/aza-Michael reaction sequence to achieve rapid construction of complex polysubstituted ring systems starting from widely available heterocyclic amine nucleophiles and carbonyl electrophiles. Notably, the diastereoselectivity of this process is enhanced by the presence of water, and DFT calculations support a stereochemical model involving a facially selective protonation of a water-coordinated enol intermediate.
- Larsen, Matthew A.,Hennessy, Elisabeth T.,Deem, Madeleine C.,Lam, Yu-Hong,Saurí, Josep,Sather, Aaron C.
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supporting information
p. 726 - 732
(2020/01/31)
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- Butadiene hydroformylation to adipaldehyde with Rh-based catalysts: Insights into ligand effects
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Rh-catalyzed hydroformylation of butadiene to adipaldehyde is a promising alternative route for producing valuable C6 compounds such as adipic acid and hexamethylenediamine. Fundamental insights into reaction pathways, aimed at enhancing adipaldehyde yield, were obtained from temporal concentration profiles and in situ ReactIR studies of butadiene hydroformylation on Rh complexes at 80 °C and 14 bar syngas (molar CO/H2 = 1) pressure in a batch reactor. Specifically, the effects of operating conditions and eight commercially available ligands on activity and selectivity were systematically investigated. It was found that the adipaldehyde selectivity is independent of the ligand/Rh ratio, rhodium concentration, butadiene concentration and syngas pressure, but significantly dependent on the type of ligand used. For example, while the DIOP ligand provided an adipaldehyde yield of ～40% with butadiene as a substrate, the 6-DPPon ligand gave a maximum adipaldehyde yield of ～93% with 4-pentenal as substrate. Furthermore, the adipaldehyde selectivity correlates well with the natural bite angle of the various ligands. ReactIR studies suggest that the preferential formation of the stable rhodium η3-crotyl complex with the various Rh complexes may be the main reason for the low adipaldehyde selectivity.
- Yu, Si-min,Snavely, William K.,Chaudhari, Raghunath V.,Subramaniam, Bala
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- Nickel-Catalyzed Selective Reduction of Carboxylic Acids to Aldehydes
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The direct reduction of carboxylic acids to aldehydes is a fundamental transformation in organic synthesis. The combination of an air-stable Ni precatalyst, dimethyl dicarbonate as an activator, and silane reductant effects this reduction for a wide variety of substrates, including pharmaceutically relevant structures, in good yields and with no overreduction to alcohols. Moreover, this methodology is scalable, allows access to deuterated aldehydes, and is also compatible with one-pot utilization of the aldehyde products.
- Iosub, Andrei V.,Morav?ík, ?tefan,Wallentin, Carl-Johan,Bergman, Joakim
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supporting information
p. 7804 - 7808
(2019/10/14)
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- Iron-Catalyzed Synthesis of α-Dienyl Five- and Six-Membered N-Heterocycles
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The iron-catalyzed synthesis of α-dienyl N-heterocycles is reported. The method is cost-effective, atom-economic, and led to a range of substituted α-dienyl heterocycles in moderate to good yields and diastereoselectivities. The α-dienyl piperidines are key synthetic intermediates as demonstrated by the preparation of a panel of α-polyenyl N-heterocycles.
- Gonnard, Laurine,Guérinot, Amandine,Cossy, Janine
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supporting information
p. 6160 - 6167
(2017/11/15)
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- Asymmetric synthesis of (+)-17-: Epi -methoxy-kauran-3-one through tandem oxidative polycyclization-pinacol process
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A synthesis of (+)-17-epi-methoxy-kauran-3-one, an O-methylated isomer of the natural diterpene 17-hydroxy-kauran-3-one, has been achieved. The strategy is based on a diastereoselective oxidative polycyclization-pinacol tandem process consisting of transforming a functionalized phenol into a compact and complex tetracycle, which represents the main core of kaurane family members. The synthesis also includes an enantioselective Yamamoto's allylation, a diastereoselective Ru-catalyzed hydrocyanation, a ring-closing metathesis and a reductive isomerization process as key steps. The structure of our synthetic substrate was determined through comparison with an O-methylated derivative of the natural compound.
- Maertens, Ga?tan,Desjardins, Samuel,Canesi, Sylvain
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supporting information
p. 6744 - 6750
(2016/07/21)
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- Formal Synthesis of Ezetimibe Using a Proline-mediated, Asymmetric, Three-component Mannich Reaction
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The formal total synthesis of ezetimibe was accomplished using a proline-mediated, asymmetric, three-component Mannich reaction as the key step. The two stereogenic centers on the β-lactam skeleton of ezetimibe were controlled by the syn-selective asymmetric Mannich reaction, followed by isomerization.
- Shimasaki, Yasuharu,Koshino, Seitaro,Hayashi, Yujiro
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supporting information
p. 30 - 32
(2016/01/20)
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- Pyrrolizidines, indolizidines and quinolizidines via a double reductive cyclisation protocol: concise asymmetric syntheses of (+)-trachelanthamidine, (+)-tashiromine and (+)-epilupinine
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The asymmetric syntheses of pyrrolizidine, indolizidine and quinolizidine alkaloids have been achieved using the diastereoselective conjugate addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide to α-alkenyl-α,β-unsaturated esters followed by diastereoselective protonation of the resultant enolates as the key stereodefining steps. The azabicyclic scaffolds were then efficiently constructed upon sequential oxidative cleavage of the olefinic units within the resultant β-amino esters and hydrogenolytic N-debenzylation of the corresponding dialdehydes, which occurs with concomitant double reductive cyclisation. Subsequent reduction of the ester moieties with LiAlH4gave (+)-trachelanthamidine, (+)-tashiromine, (1S,8aR)-1-(hydroxymethyl)octahydroindolizine and (+)-epilupinine in 4.9, 4.1, 3.0 and 5.9% overall yield, respectively, in only six steps from commercially available starting materials.
- Brambilla, Marta,Davies, Stephen G.,Fletcher, Ai M.,Roberts, Paul M.,Thomson, James E.,Zimmer, David
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p. 7417 - 7429
(2016/11/11)
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- Evidence for isomerizing hydroformylation of butadiene. A combined experimental and computational study
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The (DIOP)rhodium-catalyzed hydroformylation of butadiene has been shown to give among the highest selectivities for formation of adipaldehyde, which is useful for the synthesis of nylon. Herein, isomerizing hydroformylation is shown to be a mechanism that is partially responsible for this selectivity and density functional theory studies are used to reveal the detailed pathway for the requisite alkene isomerization.
- Maji, Tapan,Mendis, Camina H.,Thompson, Ward H.,Tunge, Jon A.
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p. 145 - 152
(2016/09/09)
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- 1H-pyrrole-2,4-dicarbonyl-derivatives and their use as flavoring agents
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The present invention primarily relates to 1H-pyrrole-2,4-dicarbonyl-derivatives of Formula (I) wherein R1, R2, R3, Z. Z' and J are as defined in the description, to mixtures thereof and to the use thereof as flavoring agents. The compounds in accordance with the present invention are suitable for producing, imparting, or intensifying an umami flavor. The invention further relates to flavoring mixtures, compositions for oral consumption as well as ready-to-eat, ready-to-use and semifinished products, comprising an effective amount of the compound of Formula (I) or of a mixture of compounds of Formula (I) and to specific methods for producing, imparting, modifying and/or intensifying specific flavor impressions.
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- Imidazo[1,2-a]pyridine-ylmethyl-derivatives and their use as flavoring agents
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The present invention primarily relates to imidazo[1,2-a]pyridine-ylmethyl-derivatives of Formula (I) wherein R1, R2, X, W e J are as defined in the description, to mixtures thereof and to the use thereof as flavoring agents. The compounds in accordance with the present invention are suitable for producing, imparting, or intensifying an umami flavor. The invention further relates to flavoring mixtures, compositions for oral consumption as well as ready-to-eat, ready-to-use and semifinished products, comprising an effective amount of the compound of Formula (I) and to specific methods for producing, imparting, modifying and/or intensifying specific flavor impressions.
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- Developing the Saegusa-Ito Cyclisation for the Synthesis of Difluorinated Cyclohexenones
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Palladium(II)-catalysed cycloalkenylation (Saegusa-Ito cyclisation) has been used for the first time to transform difluorinated silylenol ethers to difluorinated cycloalkenones under mild conditions. The silylenol ether precursors were prepared in two high-yielding steps from trifluoroethanol, and cyclised in moderate to good yields. A combination of air and copper(I) chloride in acetonitrile gave the turnover of the initial palladium(II) salt, whereas the provision of an oxygen atmosphere ensured more rapid reaction. Annulations required a minimum level of substitution on the chain, but failed when the alkene was substituted. Annelations allowed a range of n,6-bicyclic systems to be prepared and afforded three products, in which heterocycles were fused to the new cyclohexenone. The least substituted system explored underwent cyclisation followed by terminal oxidation to a cyclic enal, which corresponded to a Wacker product of unusual regiochemistry.
- Percy, Jonathan M.,McCarter, Adam W.,Sewell, Alan L.,Sloan, Nikki,Kennedy, Alan R.,Hirst, David J.
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supporting information
p. 19119 - 19127
(2016/01/26)
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- Enantioselective NHC-Catalyzed Redox [2+2] Cycloadditions with Perfluoroketones: A Route to Fluorinated Oxetanes
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The N-heterocyclic carbene (NHC) catalyzed redox formal [2+2] cycloaddition between α-aroyloxyaldehydes and perfluoroketones, followed by ring-opening in situ delivers a variety of perfluorinated β-hydroxycarbonyl compounds in good yield, and excellent diastereo- and enantioselectivity. Through a reductive work-up and subsequent cyclization, this protocol offers access to highly substituted fluorinated oxetanes in two steps and in high ee.
- Davies, Alyn T.,Slawin, Alexandra M. Z.,Smith, Andrew D.
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supporting information
p. 18944 - 18948
(2016/01/26)
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- Anti-Markovnikov Hydroamination of Homoallylic Amines
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The development of an anti-Markovnikov-selective hydroamination of unactivated alkenes is a significant challenge in organometallic chemistry. Herein, we present the rhodium-catalyzed anti-Markovnikov-selective hydroamination of homoallylic amines. The proximal Lewis basic amine serves to promote reactivity and enforce regioselectivity through the formation of the favored metallacycle, thus over-riding the inherent reactivity of the alkene. The scope of both the amine nucleophiles and homoallylic amines that participate in the reaction is demonstrated.
- Ensign, Seth C.,Vanable, Evan P.,Kortman, Gregory D.,Weir, Lee J.,Hull, Kami L.
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supporting information
p. 13748 - 13751
(2016/01/15)
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- Photocatalytic One-Pot Synthesis of Homoallyl Ketones via a Norrish Type i Reaction of Cyclopentanones
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A photocatalytic synthesis of homoallyl ketones was achieved via a one-pot procedure starting from a Norrish Type I reaction of cyclopentanones, followed by a decatungstate-catalyzed hydroacylation of electron-deficient olefins by the resulting 4-pentenals. The site-selective formyl H-abstraction in the second step can be explained by radical polar effects in the transition state.
- Okada, Megumi,Yamada, Keiichi,Fukuyama, Takahide,Ravelli, Davide,Fagnoni, Maurizio,Ryu, Ilhyong
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p. 9365 - 9369
(2015/09/28)
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- Stereoselective synthesis of quaternary carbons via the dianionic Ireland-Claisen rearrangement
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A dianionic Ireland-Claisen rearrangement of chiral, nonracemic α-methyl-β-hydroxy allylic esters has been developed that proceeds with high diastereoselectivity and provides products containing three contiguous stereogenic carbons, including a quaternary center. The potential utility of the rearrangement for complex molecule synthesis is also demonstrated.
- Crimmins, Michael T.,Knight, John D.,Williams, Philip S.,Zhang, Yan
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supporting information
p. 2458 - 2461
(2014/05/20)
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- Heterocycle synthesis based on allylic alcohol transposition using traceless trapping groups
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Allylic alcohols undergo transposition reactions in the presence of Re 2O7 whereby the equilibrium can be dictated by trapping one isomer with a pendent electrophile. Additional ionization can occur when the trapping group is an aldehyde or ketone, thus leading to cyclic oxocarbenium ion formation. Terminating the process through bimolecular nucleophilic addition into the intermediate provides a versatile method for the synthesis of diverse oxygen-containing heterocycles. Understanding the relative rates of the steps in the sequence leads to the design of reactions which create multiple stereocenters with good to excellent levels of control.
- Xie, Youwei,Floreancig, Paul E.
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supporting information
p. 4926 - 4929
(2014/05/20)
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- Low catalyst loading in ring-closing metathesis reactions
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An efficient procedure is described for ring-closing metathesis reactions. A conversion of 95 % for diethyl diallylmalonate in dilute solution could be achieved within a few minutes, reaching TOF=4173min-1, with very low loading of commercially available Ru catalysts that contained unsaturated NHC ligands. In general, only 50 to 250ppm of the catalyst is required to achieve near-quantitative conversion into a broad variety of 5-16-membered heterocyclic compounds. The practicality of this procedure was illustrated in the synthesis of 5-8-membered N-tert-butoxycarbonyl (N-Boc)- and N-para-toluenesulfonyl (N-Ts)-protected cyclic amines and 9-16-membered lactones. The synthesis of macrocyclic proline-based lactams required slightly higher catalyst loadings. Along with monocyclic products, oligomeric byproducts, mostly cyclodimers, were isolated and characterized. Getting some closure: An efficient procedure is described for ring-closing metathesis reactions in which only 50 to 250ppm of catalyst is required to effect almost-quantitative conversion into a broad range of 5-16-membered heterocyclic compounds. The practicality of this procedure was illustrated in the synthesis of 5-8-membered N-protected cyclic amines, 9-16-membered lactones, and 11-16-membered proline-based lactams. Copyright
- Kadyrov, Renat
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supporting information
p. 1002 - 1012
(2013/02/23)
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- THIOL-ENE CLICK CHEMISTRY FOR DRUG CONJUGATES
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The present invention relates to linker molecules that readily conjugate cellular recognition ligand at one end and drug payload at the other, and are useful in treating or preventing cancer, an autoimmune disease, an inflammatory condition, a central nervous system disorder or an infection. The linker inker molecules of the invention are represented by Formula I, II and III; Linker-Drug compounds represented by Formula IV, V and VI; and Ligand-Linker-Drug conjugates represented by Formula VII, VIII and IX:
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Paragraph 0280; 0281
(2014/01/07)
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- Catalytic enantioselective formal Hetero-Diels-Alder reactions of enones with isatins to give spirooxindole tetrahydropyranones
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Organocatalytic formal hetero-Diels-Alder reactions of enones with isatins, which gave highly enantiomerically enriched functionalized spirooxindole tetrahydropyranones via an enamine-based mechanism, were developed. The catalyst systems were identified by a screen of combinations of amines, acids, and additives. With the identified catalyst systems, various spirooxindole tetrahydropyranones were synthesized in high yields with high diastereo- and enantioselectivities (see scheme). Copyright
- Cui, Hai-Lei,Tanaka, Fujie
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supporting information
p. 6213 - 6216
(2013/07/04)
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- Hypervalent iodine/TEMPO-mediated oxidation in flow systems: A fast and efficient protocol for alcohol oxidation
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Hypervalent iodine(III)/TEMPO-mediated oxidation of various aliphatic, aromatic and allylic alcohols to their corresponding carbonyl compounds was successfully achieved by using microreactor technology. This method can be used as an alternative for the oxidation of various alcohols achieving excellent yields and selectivities in significantly shortened reaction times.
- Ambreen, Nida,Kumar, Ravi,Wirth, Thomas
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p. 1437 - 1442
(2013/08/23)
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- Diversity-oriented synthesis of hydrazine-derived compounds from amino isocyanates generated in situ
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Behind the mask: Nitrogen-substituted isocyanates are rare and their synthetic potential is virtually untapped. Simple masked precursors can form amphoteric amino isocyanate intermediates in situ, and allows the synthesis of complex hydrazine derivatives upon addition with amines. This reactivity was used in a cascade substitution/hydroamination sequence, and in the assembly of azadipeptide analogues. Copyright
- Clavette, Christian,Vincent Rocan, Jean-Francois,Beauchemin, Andre M.
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supporting information
p. 12705 - 12708
(2013/12/04)
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- Construction of enantioenriched cyclic compounds by asymmetric allylic alkylation and ring-closing metathesis
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A new approach to highly enantioenriched cyclic compounds (up to 98a€‰% ee) has been developed by using ω-ethylenic allylic substrates in a one-pot asymmetric allylic alkylation and ring-closing metathesis sequence. The starting compounds are synthetic equivalents of cyclic allylic substrates. The method is exemplified with both Cu and Ir catalysts, and chiral phosphoramidite ligands. A new approach to highly enantioenriched cyclic compounds (up to 98a€‰% ee) has been developed by using ω-ethylenic allylic substrates in a one-pot asymmetric allylic alkylation and ring-closing metathesis sequence. The starting compounds are synthetic equivalents of cyclic allylic substrates. The method is exemplified with both Cu and Ir catalysts, and chiral phosphoramidite ligands. Copyright
- Giacomina, Francesca,Alexakis, Alexandre
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supporting information
p. 6710 - 6721
(2013/11/06)
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- TEMPO-mediated electrooxidation of primary and secondary alcohols in a microfluidic electrolytic cell
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A general procedure for the 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-mediated electrooxidation of primary and secondary alcohols modified for application in a microfluidic electrolytic cell is described. The electrocatalytic system utilises a buffered aqueous tert-butanol reaction medium, which operates effectively without the requirement for additional electrolyte, providing a mild protocol for the oxidation of alcohols to aldehydes and ketones at ambient temperature on a laboratory scale. Optimisation of the process is discussed along with the oxidation of 15 representative alcohols. TEMPO and no salt in sight: A general procedure for the 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO)-mediated electrooxidation of primary and secondary alcohols modified for application in a microfluidic electrolytic cell is described. The reaction is performed at ambient temperature in buffered aqueous tBuOH without additional electrolyte. Copyright
- Hill-Cousins, Joseph T.,Kuleshova, Jekaterina,Green, Robert A.,Birkin, Peter R.,Pletcher, Derek,Underwood, Toby J.,Leach, Stuart G.,Brown, Richard C. D.
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experimental part
p. 326 - 331
(2012/05/07)
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- Diastereoselective synthesis of aliphatic α,α-difluoro- β3-amino esters via a sonocatalyzed Reformatsky reaction
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(R)-2-Phenylglycine ethyl ester was found to be a cheap and effective auxiliary for the preparation of aliphatic α,α-difluoro- β3-amino esters via a Reformatsky reaction performed under sonication conditions. The products were obtained in good to high yield and ≥96:4 dr, thus providing a new stereoselective route to this under-represented class of compounds. A facile one-pot removal of the phenylglycine moiety and concomitant Boc protection subsequently afforded the corresponding Boc-protected β3-amino esters in excellent yield.
- March, Taryn L.,Johnston, Martin R.,Duggan, Peter J.
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supporting information; experimental part
p. 182 - 185
(2012/02/16)
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- Total syntheses of amphidinolides B, G, and H
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Not one, not two, but three: Total syntheses of amphidinolides B, G, and H, which exhibit strong, nanogram-scale cytotoxicity against various tumor cell lines, have been executed. The synthetic strategy relied on implementation of a diene construction protocol and a diastereoselective aldol process. The 26- and 27-membered macrocyclic lactone rings were efficiently constructed by using ring-closing metathesis (RCM). Copyright
- Hara, Akihiro,Morimoto, Ryo,Iwasaki, Yuki,Saitoh, Tsuyoshi,Ishikawa, Yuichi,Nishiyama, Shigeru
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supporting information
p. 9877 - 9880
(2012/11/07)
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- Formal total synthesis of (-)-5,6-dihydrocineromycine B
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An efficient and highly convergent formal total synthesis of the 14-membered macrolide (-)-5,6-dihydrocineromycine B is achieved. Key reaction sequences include a Sharpless asymmetric epoxidation followed by esterification for the formation of a fully functionalized acyclic precursor, Corey-Bakshi-Shibata reduction, and ring-closing metathesis, respectively. Georg Thieme Verlag KG Stuttgart · New York.
- Reddy, G. Venkateswar,Kumar, R. Sateesh Chandra,Siva,Babu, K. Suresh,Rao, J. Madhusudana
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p. 2677 - 2681
(2013/01/15)
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- A total synthesis of herboxidiene methyl ester
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The total synthesis of the methyl ester, 35, of herboxidiene (1, a.k.a. GEX1A and TAN-1609), a polyketide displaying both herbicidal and anti-tumor activity, is described. The convergent reaction sequence involves, in its closing stages, the union of the phosphine oxide 3 with the aldehyde 21 to deliver, via a Horner-Wittig reaction with accompanying epimerization at C12, compound 33 that after deprotection affords an alcohol, 34, capable of participating in a regioand diastereo-selective epoxidation reaction to give target 35. Phosphine oxide 3 was prepared via the intramolecular hetero-Michael addition of a secondary alcohol to a tethered and Z-configured acrylate while aldehyde 21 was generated, in the crucial step of the relevant reaction sequence, via an Ireland-Claisen rearrangement reaction.
- Premraj, Rajaratnam,McLeod, Malcolm D.,Simpson, Gregory W.,Banwell, Martin G.
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p. 2949 - 2976
(2013/02/21)
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- Cascade cyclization, dipolar cycloaddition to bridged tricyclic amines related to the daphniphyllum alkaloids
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A tandem one-pot reaction of an aldehyde with a primary amine involving condensation and then cyclization (N-alkylation), followed by intramolecular dipolar cycloaddition of the resulting nitrone or azomethine ylide, provides a synthesis of bridged tricyclic amines. The reaction was most successful using hydroxylamine, and when the dipolarophile was an unsaturated ester, subsequent reduction of the N-O bond and cyclization to the lactam provided the core ring system of the yuzurimine, daphnilactone B, and bukittinggine type Daphniphyllum alkaloids.
- Coldham, Iain,Burrell, Adam J. M.,Guerrand, Helene D. S.,Oram, Niall
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supporting information; experimental part
p. 1267 - 1269
(2011/04/26)
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- Novel entry to the tricyclic core of stemofoline and didehydrostemofoline
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A novel approach to the tricyclic core of the Stemona alkaloids stemofoline and didehydrostemofoline has been discovered that features an intramolecular (3+2) dipolar cycloaddition of an unactivated carbon-carbon double bond with an azomethine ylide; the azomethine ylide was generated by an unprecedented reaction that occurred during a Swern oxidation of an α-(N-cyanomethyl)- β-hydroxy ester. In separate experiments, the efficacy of introducing the requisite oxygen functionality at C(8) and the 1-butenyl side chain at C(3) was established.
- Dietz, Jochen,Martin, Stephen F.
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supporting information; experimental part
p. 2048 - 2050
(2011/05/09)
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- Conjugate reduction and reductive aldol cyclization of α,β- unsaturated thioesters catalyzed by (BDP)CuH
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A conjugate reduction of α,β-unsaturated thioesters catalyzed by copper hydride using PMHS as stoichiometric reductant has been developed. 1,2-Bis(diphenylphosphino)benzene (BDP) was the most effective ligand for this reduction. Saturated thioesters could be produced in excellent yields when the substituent on the thiol is not sterically-demanding. This protocol was applied to induce the reductive aldol cyclization of keto-enethioates, which could offer β-hydroxythioesters in moderate to good yields.
- Li, Ninglin,Ou, Jun,Miesch, Michel,Chiu, Pauline
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supporting information; experimental part
p. 6143 - 6147
(2011/10/08)
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- Tandem catalysis of ring-closing metathesis/ atom transfer radical reactions with homobimetallic ruthenium-arene complexes
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The tandem catalysis of ring-closing metathesis/atom transfer radical reactions was investigated with the homobimetallic ruthenium-indenylidene complex [(p-cymene)Ru(μ-Cl)3RuCl(3-phenyl-1-indenylidene)(PCy 3)] (1) to generate active species in situ. The two catalytic processes were first carried out independently in a case study before the whole sequence was optimized and applied to the synthesis of several polyhalogenated bicyclic γ-lactams and lactones from αω-diene substrates bearing trihaloacetamide or trichloroacetate functionalities. The individual steps were carefully monitored by 1H and 31P NMR spectroscopies in order to understand the intimate details of the catalytic cycles. Polyhalogenated substrates and the ethylene released upon metathesis induced the clean transformation of catalyst precursor 1 into the Ru(II)-Ru(III) mixed-valence compound [(p- cymene)Ru(μ-Cl)3RuCl 2(PCy3)], which was found to be an efficient promoter for atom transfer radical reactions under the adopted experimental conditions.
- Borguet, Yannick,Sauvage, Xavier,Zaragoza, Guillermo,Demonceau, Albert,Delaude, Lionel
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supporting information; experimental part
p. 1167 - 1173
(2011/04/15)
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- Palladium-catalyzed coupling reactions of thioimidate N-oxides: Access to α-alkenyl- And α-aryl-functionalized cyclic nitrones
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(Figure Presented) Surprisingly useful are thioimidate Noxides in the preparation of aryl- and vinylsubstituted cyclic ketonitrones through the Liebeskind-Srogl reaction. This novel synthetic approach appears to be efficient and have a broad scope (see scheme).
- Schleiss, Julie,Rollin, Patrick,Tatiboueet, Arnaud
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scheme or table
p. 577 - 580
(2010/04/05)
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- ω-Ethylenic allylic substrates as alternatives to cyclic substrates in copper- and iridium-catalyzed asymmetric allylic alkylation
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"Chemical Equation Presented" A new strategy to access highly enantioenriched cyclic compounds (up to 98%) Is proposed using ω-ethylenic allylic substrates through a one-pot asymmetric allylic alkylation and ring-closing metathesis. Such starting compounds can be seen as synthetic equivalents of cyclic allylic substrates.
- Giacomina, Francesca,Riat, David,Alexakis, Alexandre
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supporting information; scheme or table
p. 1156 - 1159
(2010/05/18)
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- A three-step tandem process for the synthesis of bicyclic γ-lactams
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A one-pot, three-step tandem process has been developed for the direct synthesis of functionalised bicyclic [3.3.0], [4.3.0] and [5.3.0] γ-lactams from simple allylic trichloroacetimidates. The process involves a palladium(ii) mediated Overman rearrangement followed by the use of Grubbs first generation complex which catalyzes both a ring closing metathesis reaction and a Kharasch cyclization. As well as exploring the scope of this process for the synthesis of a range of functionalised bicyclic γ-lactams, the use of chiral palladium(ii) catalysts during the Overman rearrangement for the enantioselective synthesis of the bicyclic γ-lactams is also demonstrated. The Royal Society of Chemistry 2010.
- McGonagle, Fiona I.,Brown, Lindsay,Cooke, Andrew,Sutherland, Andrew
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experimental part
p. 3418 - 3425
(2010/08/21)
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- Multicatalytic synthesis of complex tetrahydrofurans involving bismuth(iii) triflate catalyzed intramolecular hydroalkoxylation of unactivated olefins
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A multicatalytic synthesis of complex tetrahydrofurans has been developed involving a Bi(OTf)3-catalyzed nucleophilic addition/ hydroalkoxylation sequence. Complex tetrahydrofuranyl products may be formed rapidly in high yield and with good diastereoselectivity. The demonstrated scope of hydroalkoxylation has also been expanded to include substrates bearing useful functional handles including carboxylate ester, olefin, nitrile, and nitro groups.
- Kelly, Brendan D.,Allen, Julia M.,Tundel, Rachel E.,Lambert, Tristan H.
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supporting information; experimental part
p. 1381 - 1383
(2009/10/02)
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- Hydrazides as tunable reagents for alkene hydroamination and aminocarbonylation
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(Chemical Equation Presented) Benzoic hydrazides (R = Ph), which are remarkably bench and thermally stable reagents (often up to 230°C), afford intramolecular hydroamination products upon heating at high temperatures (120-235°C). A concerted Cope-type hydroamination event, followed by a hydrazide-mediated proton transfer step of the hydrazinium ylide intermediate, is proposed and supported by DFT calculations. In contrast, a simple modification of the reagent structure (R = Ot-Bu or NH2) favors the formation of aminocarbonylation products at 200°C, and the latter reaction is shown to be stereospecific. Copyright
- Roveda, Jean-Gregoire,Clavette, Christian,Hunt, Ashley D.,Gorelsky, Serge I.,Whipp, Christopher J.,Beauchemin, Andre M.
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supporting information; experimental part
p. 8740 - 8741
(2009/12/04)
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- Catalytic aerobic oxidation of allylic alcohols to carbonyl compounds under mild conditions
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A new catalytic aerobic oxidation of alcohols to aldehydes under green conditions was developed (room temperature and pressure, water solution, open vials). The water-soluble platinum(II) tetrasulfophthalocyanine (PtPcS) catalyst showed the best selectivity for carbonyl derivatives, and in particular for α,β-unsaturated alcohols; the reactions are slow.
- Tonucci, Lucia,Nicastro, Marco,D'Alessandro, Nicola,Bressan, Mario,D'Ambrosio, Primiano,Morvillo, Antonino
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experimental part
p. 816 - 820
(2010/04/23)
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- An intramolecular Diels-Alder strategy for the asbestinins: Enantioselective total syntheses of 11-acetoxy-4-deoxyasbestinin D and asbestinin-12
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(Chemical Equation Presented) The enantioselective total syntheses of 11-acetoxy-4-deoxyasbestinin D and asbestinin-12 have been completed. A glycolate aldol reaction provided a diene useful for ring-closing metathesis to form an oxonene, which was ultimately employed as a template to execute a highly stereoselective intramolecular Diels-Alder cycloaddition, forming the hydroisobenzofuran moiety. The absolute configuration of the asbestinin subclass was confirmed via these synthetic efforts.
- Crimmins, Michael T.,Ellis, J. Michael
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p. 1649 - 1660
(2008/09/18)
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- Copper-catalyzed 1,2-double amination of 1-halo-1-alkynes. Concise synthesis of protected tetrahydropyrazines and related heterocyclic compounds
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Reaction of N,N′-di(p-toluenesulfonyl)-1,2-diamine, 1-bromo-1-alkyne, K3PO4, and a catalytic amount of CuI in hot DMF afforded N,N′-di(p-toluenesulfonyl)-1,2,3,4-tetrahydropyrazines in good yields. The reaction most likely involves (i) monoalkynylation of the diamine derivative with 1-bromo-1-alkyne, and (ii) 6-endo-dig ring closure between the acetylenic bond and another sulfonylamine moiety of the diamine. When the starting 1,2-diamine derivative was replaced with N,N′-di(p-toluenesulfonyl)-1,3-diamine or N-(p-toluenesulfonyl)-2-amino-1-ethanol, the corresponding seven-membered diazacycle or six-membered N,O-heterocycle was produced. In addition, 1,1-dibromo-1-alkene could be used in place of 1-bromo-1-alkyne. Copyright
- Fukudome, Yasuhiro,Naito, Hiroyuki,Hata, Takeshi,Urabe, Hirokazu
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p. 1820 - 1821
(2008/09/18)
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- Synthesis, antiviral activity, and conformational studies of a P3 aza-peptide analog of a potent macrocyclic tripeptide HCV protease inhibitor
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BILN 2061 is a macrocyclic tripeptide inhibitor of hepatitis C virus NS3-4A protease that has shown efficacy in the clinic for treating patients infected with HCV. We have synthesized a P3 aza-peptide analog of a potent macrocyclic tripeptide inhibitor closely related to BILN 2061. This aza-derivative was found to be >2 orders of magnitude less active than the parent macrocycle in both isolated enzyme (HCV NS3-4A) and HCV subgenomic replicon assays. NMR studies of P3 aza-peptides revealed these compounds adopt a β-turn conformation stabilized by an intramolecular H-bonding interaction. Molecular models of these structures indicate a d-like configuration of the P3 aza-residue. Thus, the configurationally undefined nature at P3 in the aza-peptide allows the compound to adopt an H-bond stabilized conformation that is substantially different from that necessary for tight binding to the active site of HCV NS3 protease.
- Randolph, John T.,Zhang, Xiaolin,Huang, Peggy P.,Klein, Larry L.,Kurtz, Kevin A.,Konstantinidis, Alex K.,He, Wenping,Kati, Warren M.,Kempf, Dale J.
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p. 2745 - 2750
(2008/12/21)
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- Tishchenko reactions of aldehydes promoted by diisobutylaluminum hydride and its application to the macrocyclic lactone formation
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Aliphatic aldehydes react with catalytic amount of Dibal-H in n-pentane to give the corresponding Tishchenko products in good to excellent yields. On contrary, α-silyloxy aldehydes give α-silyloxy ketones via Oppenauer oxidation under similar condition. Tishchenko reaction of ω-alkene aldehydes followed by RCM and hydrogenation affords a convenient method to prepare the 11-37 membered macrocyclic lactones.
- Hon, Yung-Son,Wong, Ying-Chieh,Chang, Chun-Ping,Hsieh, Cheng-Han
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p. 11325 - 11340
(2008/03/12)
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- A tandem aza-claisen rearrangement and ring closing metathesis reaction for the synthesis of cyclic allylic trichloroacetamides
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(Chemical Equation Presented) A one-pot tandem palladium(II)-catalyzed aza-Claisen rearrangement and ring closing metathesis process has been developed for the efficient synthesis of cyclic allylic trichloroacetamides. The use of chiral Pd(II) catalysts such as (S)-COP-Cl during the rearrangement stage results in the preparation of these compounds in excellent yields and in high enantiomeric excess.
- Swift, Michael D.,Sutherland, Andrew
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p. 5239 - 5242
(2008/09/17)
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