Exo‐Dig Radical Cascades of Skipped Enediynes: Building a Naphthalene Moiety within a Polycyclic Framework

Cascade radical transformations of acyclic precursors open efficient, convenient and atom‐economical access to functionalized compounds of increased structural complexity. This report describes a selective sequence of 5‐exo‐dig and 6‐exo‐dig cyclizations followed by attack at a pendant aromatic moiety and rearomatization.     

Stereoselective synthesis and polymerization of Exo‐5‐trimethylsilylnorbornene

Herein the stereoselective two‐step synthesis of pure exo‐5‐trimethylsilylnorbornene is reported. The monomer proved to be highly reactive in both metathesis and addition polymerization. ROMP polymerization was catalyzed by the first‐generation Grubbs catalyst. High‐molecular‐weight saturated addition polymers were prepared using nickel or palladium complexes as precatalysts and Na⁺[B(3,5‐(CF₃)₂C₆H₃)₄]⁻ and/or MAO as cocatalysts. The obtained addition polynorbornenes are highly gas permeable and microporous materials possessing large free volume and BET surface area (up to 540 m²/g). The influence of the substituent orientation (exo‐ vs. exo‐/endo‐mixture) on polymer properties was established. The metathesis polymer based on exo‐isomer exhibits 1.5‐ to 2‐fold increase of permeability coefficients for all gases in comparison to the similar polymer based on the mixture of exo‐ and endo‐isomers. © 2018 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018 , 56, 1234–1248     

Synthesis of Anionic Phosphorus‐Containing Heterocycles by Intramolecular Cyclizations Involving N‐Functionalized Phosphinecarboxamides

We report that the 2‐phosphaethynolate anion (PCO^?) reacts with propargylamines in the presence of a proton source to afford novel N‐derivatized phosphinecarboxamides bearing alkyne functionalities. Deprotonation of these species gives rise to novel five‐ and six‐membered anionic heterocycles resulting from intramolecular nucleophilic attack of the resulting phosphide at the alkyne functionality (via 5‐exo‐dig or 6‐endo‐dig cyclizations, respectively). The nature of the substituents on the phosphinecarboxamide can be used to influence the outcome of these reactions. This strategy represents a unique approach to phosphorus‐containing heterocylic systems that are closely related to known organic molecules with interesting bio‐active properties.     

The Synthesis and Chemistry of 1,3‐Bridged Polycyclic Cyclopropenes: 8‐Oxatricyclo[3.2.1.02,4]octa‐2,6‐dienes

Three 1,3‐bridged polycyclic cyclopropenes, exo‐8‐oxatricyclo[3.2.1.0^2,4]octa‐2,6‐diene ( 10 ), endo‐8‐oxatricyclo[3.2.1.0^2,4]octa‐2,6‐diene ( 11 ), and exo‐6,7‐benzo‐1,5‐diphenyl‐8‐oxatricyclo[3.2.1.0^2,4]octa‐2,6‐diene ( 12 ), have been synthesized by elimination of 2‐chloro‐3‐trimethylsilyl‐8‐oxatricyclo[3.2.1.0^2,4]‐oct‐6‐enes, 17 , 18 and 30 , which were generated from 1‐chloro‐3‐trimethylsilylcyclopropene with furan and diphenylisobenzofuran. We have demonstrated a facile route to synthesize the highly strained 1,3‐fused polycyclic cyclopropenes, 10 , 11 , and 12 . The stereochemistry of the Diels‐Alder reactions of cyclopropene 16 with furan and DPIBF are different. Cyclopropene 16 was treated with furan to form exo‐exo and endo‐exo adducts (5:2) and treated with DPIBF to generate an exo‐exo adduct. Compounds 10 , 11 and 12 undergo isomerization reactions to form benzaldehyde and phenyl 4‐phenyl‐[1]naphthyl ketone to release strain energies via diradical mechanisms.     

Efficient Synthesis of Substituted 3‐Azabicyclo[3.1.0]hexan‐2‐ones from 2‐Iodocyclopropanecarboxamides Using a Copper‐Free Sonogashira Coupling

The copper‐free Sonogashira coupling between N‐substituted cis‐ 2‐iodocyclopropanecarboxamides and terminal aryl‐, heteroaryl‐alkynes or enynes, followed by 5‐exo‐dig cyclization of the nitrogen amide onto the carbon–carbon triple bond, provides a remarkably efficient access to a variety of substituted 4‐methylene‐3‐azabicyclo[3.1.0]hexan‐2‐ones in excellent yields. Protonation of these latter enamides generates bicyclic N‐acyliminium ions that can be involved in Pictet–Spengler cyclizations leading to new 3‐azabicyclo[3.1.0]hexan‐2‐ones, possessing a quaternary stereocenter at C4, with high diastereoselectivities. This strategy constitutes an attractive complementary alternative to the classical route that relies on the addition of organometallic reagents to cyclopropyl imides.     

A Versatile Synthesis of β‐Lactam‐Fused Oxacycles through the Palladium‐Catalyzed Chemo‐, Regio‐, and Diastereoselective Cyclization of Allenic Diols

Chemo‐, regio‐ and stereocontrolled palladium‐catalyzed preparations of enantiopure morpholines, oxocines, and dioxonines have been developed starting from 2‐azetidinone‐tethered γ,δ‐, δ,ε‐, and ε,ζ‐allendiols. The palladium‐catalyzed cyclizative coupling reaction of γ,δ‐allendiols 2 with allyl bromide or lithium bromide was effective as 8‐endo cyclization by attack of the primary hydroxy group to the terminal allene carbon to afford enantiopure functionalized oxocines; whereas the palladium‐catalyzed cyclizative coupling reaction of 2‐azetidinone‐tethered ε,ζ‐allendiols 4 furnished dioxonines 16 through a totally chemo‐ and regioselective 9‐endo oxycyclization. By contrast, the palladium‐catalyzed cyclizative coupling reaction of 2‐azetidinone‐tethered δ,ε‐allendiols 3 with aryl and alkenyl halides exclusively generated six‐membered‐ring compounds 14 a and 15 a . These results could be explained through a 6‐exo cyclization by chemo‐ and regiospecific attack of the secondary hydroxy group to the internal allene carbon. Chemo‐ and regiocontrol issues are mainly influenced by the length of the tether rather than by the nature of the metal catalysts and substituents. This reactivity can be rationalized by means of density functional theory calculations.     

1‐Bromo‐2‐(cyclopropylidenemethyl)benzene: A Useful Building Block in the Palladium‐Catalyzed Reaction of 2‐Alkynylbenzenamine

A novel palladium‐catalyzed domino reaction of 1‐bromo‐2‐(cyclopropylidenemethyl)benzene and 2‐alkynylbenzenamine is reported, which generates 2‐(naphthalen‐2‐yl)benzenamines and 5H‐indeno[1,2‐c]quinolines via 6‐endo and 5‐exo cyclization, respectively. The regioselectivity for the final outcome can be affected by phosphine and N‐heterocyclic carbene ligands.     

Pyrrolidines and Piperidines by Ligand‐Enabled Aza‐Heck Cyclizations and Cascades of N‐(Pentafluorobenzoyloxy)carbamates

Ligand‐enabled aza‐Heck cyclizations and cascades of N‐(pentafluorobenzoyloxy)carbamates are described. These studies encompass the first examples of efficient non‐biased 6‐exo aza‐Heck cyclizations. The methodology provides direct and flexible access to carbamate protected pyrrolidines and piperidines.     

Palladium‐Catalyzed Oxidative Cycloisomerization of 2‐Cinnamyl‐1,3‐Dicarbonyls: Synthesis of Functionalized 2‐Benzyl Furans

A new palladium‐catalyzed intramolecular oxidative cycloisomerization of readily available starting materials, 2‐cinnamyl‐1,3‐dicarbonyls, has been demonstrated for the creation of structurally diverse 2‐benzyl furans. The cycloisomerization occurs by a regioselective 5‐exo‐trig pathway. The reaction shows a broad substrate scope with good to excellent yields. Furthermore, a one‐pot procedure has been executed by using readily available cinnamyl alcohols and 1,3‐diketones.     

Radical 4‐exo Cyclizations via Template Catalysis

The mechanism of catalytic 4‐exo cyclizations without gem‐dialkyl substitution was investigated by a comparison of cyclic voltammetry, EPR, and computational studies with previously published synthetic results. The most active catalyst is a super‐unsaturated 13‐electron titanocene(III) complex that is formed by supramolecular activation through hydrogen bonding. The template catalyst binds radicals via a two‐point binding that is mandatory for the success of the 4‐exo cyclization. The computational investigations revealed that formation of the observed trans‐cyclobutane product is not possible from the most stable substrate radical. Instead, the most stable product is formed with the lowest energy of activation from a disfavored substrate in a Curtin–Hammett related scenario.     

Radical 4‐exo Cyclizations onto O‐Alkyloxime Acceptors: Towards the Synthesis of Penicillin‐Containing Antibiotics

The 4‐exo cyclizations of two types of carbamoyl radicals onto O‐alkyloxime acceptor groups were studied as potential routes to 3‐amino‐substituted azetidinones and hence to penicillins. A general synthetic route to ‘benzaldehyde oxime oxalate amides’ (= 2‐[(benzylideneamino)oxy]‐2‐oxoacetamides; see, e.g., 10c ) of 2‐{[(benzyloxy)imino]methyl}‐substituted thiazolidine‐4‐carboxylic acid methyl esters 9 was developed (Scheme 3). It was shown by EPR spectroscopy that these compounds underwent sensitized photodissociation to the corresponding carbamoyl radicals but that these did not ring close. An analogous open‐chain precursor, benzaldehyde O‐(benzylaminoacetaldehyde‐O‐benzyloxalyl)oxime, 15 , lacking the 5‐membered thiazolidine ring, was shown by EPR spectroscopy to release the corresponding carbamoyl radical (Scheme 4). The latter underwent 4‐exo cyclization onto its C?NOBn bond in non‐H‐atom donor solvents. The rate constant for this cyclization was determined by the steady‐state EPR method. Spectroscopic evidence indicated that the reverse ring‐opening process was slower than cyclization.     

Competitive Gold‐Promoted Meyer–Schuster and oxy‐Cope Rearrangements of 3‐Acyloxy‐1,5‐enynes: Selective Catalysis for the Synthesis of (+)‐(S)‐γ‐Ionone and (−)‐(2S,6 R)‐cis‐γ‐Irone

We report a simple, highly stereoselective synthesis of (+)‐(S)‐γ‐ionone and (‐)‐(2S,6R)‐cis‐γ‐irone, two characteristic and precious odorants; the latter compound is a constituent of the essential oil obtained from iris rhizomes. Of general interest in this approach are the photoisomerization of an endo trisubstituted cyclohexene double bond to an exo vinyl group and the installation of the enone side chain through a [(NHC)Au^I]‐catalyzed Meyer–Schuster‐like rearrangement. This required a careful investigation of the mechanism of the gold‐catalyzed reaction and a judicious selection of reaction conditions. In fact, it was found that the Meyer–Schuster reaction may compete with the oxy‐Cope rearrangement. Gold‐based catalytic systems can promote either reaction selectively. In the present system, the mononuclear gold complex [Au(IPr)Cl], in combination with the silver salt AgSbF₆ in 100:1 butan‐2‐one/H₂O, proved to efficiently promote the Meyer–Schuster rearrangement of propargylic benzoates, whereas the digold catalyst [{Au(IPr)}₂(μ‐OH)][BF₄] in anhydrous dichloromethane selectively promoted the oxy‐Cope rearrangement of propargylic alcohols.     

Cu‐Catalyzed Aerobic Oxidative Cyclizations of 3‐N‐Hydroxyamino‐1,2‐propadienes with Alcohols,Thiols, and Amines To Form α‐O‐, S‐, and N‐Substituted 4‐Methylquinoline Derivatives

A one‐pot, two‐step synthesis of α‐O‐, S‐, and N‐substituted 4‐methylquinoline derivatives through Cu‐catalyzed aerobic oxidations of N‐hydroxyaminoallenes with alcohols, thiols, and amines is described. This reaction sequence involves an initial oxidation of N‐hydroxyaminoallenes with NuH (Nu=OH, OR, NHR, and SR) to form 3‐substituted 2‐en‐1‐ones, followed by Brønsted acid catalyzed intramolecular cyclizations of the resulting products. Our mechanistic analysis suggests that the reactions proceed through a radical‐type mechanism rather than a typical nitrone‐intermediate route. The utility of this new Cu‐catalyzed reaction is shown by its applicability to the synthesis of several 2‐amino‐4‐methylquinoline derivatives, which are known to be key precursors to several bioactive molecules.     

Rhodium‐Catalyzed Cascade Reaction of 1,6‐Enynes Involving Addition,Cyclization, and β‐Oxygen Elimination

The reaction of arylboronic acids with 1,6‐enynes that contain an allylic ether moiety is catalyzed by a rhodium(I) complex to produce cyclopentanes with a tetrasubstituted exo olefin and a pendant vinyl group. The reaction is initiated by the regioselective addition of an arylrhodium(I) species to the carbon–carbon triple bond of the 1,6‐enyne. The resulting alkenylrhodium(I) compound subsequently undergoes intramolecular carborhodation of the allylic double bond in a 5‐exo‐trig mode. β Elimination of the methoxy group affords the cyclization product and the catalytically active methoxorhodium(I) species. The use of alkyl Grignard reagents instead of arylboronic acids as organometallic nucleophiles was also examined.     

Syntheses,antitumor activities,and antiangiogenesis of exo‐3,6‐epoxy‐1,2,3,6‐tetrahydrophthalimidoethanoyl‐ 5‐fluorouracil and its polymers

A new monomer, exo‐3,6‐epoxy‐1,2,3,6‐tetrahydrophthalimidoethanoyl‐5‐fluorouracil (ETFU), was synthesized by the reaction of exo‐3,6‐epoxy‐1,2,3,6‐tetrahydrophthalimidoethanoyl chloride (ETPC) and 5‐fluorouracil (5‐FU). The homopolymer of ETFU and its copolymers with acrylic acid (AA) and vinyl acetate (VAc) were prepared via photopolymerizations with 2,2‐dimethoxy‐2‐phenylacetophenone at 25 °C for 48 h. The structures of the synthesized monomer and polymers were identified by Fourier transform infrared, ¹H NMR, and ¹³C NMR spectroscopy and elemental analysis. The ETFU contents in poly(ETFU‐co‐AA) and poly(ETFU‐co‐VAc) were 26 mol % and 26 mol %, respectively. The number‐average molecular weights of the polymers, as determined by gel permeation chromatography, ranged from 5600 to 17,000. The in vitro cytotoxicities of 5‐FU and the synthesized samples against mouse mammary carcinoma and human histiocytic lymphoma cancer cell lines increased in the following order: ETFU > 5‐FU > poly(ETFU‐co‐AA) > poly(ETFU) > poly(ETFU‐co‐VAc). The in vivo antitumor activities of the polymers against Balb/C mice bearing the sarcoma 180 tumor cells were greater than those of 5‐FU at all doses tested. The inhibitions of the samples for SV40 DNA replication and antiangiogenesis were much greater than the inhibition of the control. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 4272–4281, 2000     

Ironcarbonyl‐Mediated Alkene Hydroamidation of 7‐Oxabenzonorbornadiene

Iron carbonyl‐mediated alkene hydroamidation of 7‐oxabenzonorbornadiene was accomplished under very mild conditions as the result of nucleophilic attack of amines on iron‐coordinating CO to produce exo‐5‐(alkylaminocarbonyl)‐7‐oxabenzobicyclo[2.2.1]hept‐2‐ene derivatives.     

Pd‐Catalyzed Selective Bifunctionalization of 3‐Iodo‐o‐Carborane by Pd Migration

A palladium‐catalyzed highly selective 3,4‐bifunctionalization of 3‐I‐o‐carborane has been developed, leading to the preparation of 3‐alkenyl‐4‐R‐o‐carboranes (R=alkyl, alkynyl, aryl, allyl, CN, and amido) in high to excellent yields. This protocol combines the sequential activation of cage B(3)?I and B(4)?H bonds by Pd migration from exo‐alkenyl sp² C to cage B(4), which is driven by thermodynamic force. This represents a brand‐new strategy for selective bifunctionalization of carboranes with two different substituents.     

Asymmetric Construction of Pyrrolidines Bearing a Trifluoromethylated Quaternary Stereogenic Center via CuI‐Catalyzed 1,3‐Dipolar Cycloaddition of Azomethine Ylides with β‐CF3‐β,β‐Disubstituted Nitroalkenes

A direct and convenient method has been developed for the synthesis of optically active pyrrolidines bearing a quaternary stereogenic center containing a CF₃ group at the C‐3 position of the pyrrolidine ring. The synthesis system, Cu^I/Si‐FOXAP‐catalyzed exo‐selective 1,3‐dipolar cycloaddition of azomethine ylides with β‐CF₃‐β,β‐disubstituted nitroalkenes, provides pyrrolidines with high diastereoselectivities (up to >98:2 d.r.) and excellent enantioselectivities (up to >99.9 ee) and performs well for a broad scope of substrates under mild conditions.     

Polyether Natural Product Inspired Cascade Cyclizations: Autocatalysis on π‐Acidic Aromatic Surfaces

Anion‐π catalysis functions by stabilizing anionic transition states on aromatic π surfaces, thus providing a new approach to molecular transformation. The delocalized nature of anion–π interactions suggests that they serve best in stabilizing long‐distance charge displacements. Aiming therefore for an anionic cascade reaction that is as charismatic as the steroid cyclization is for conventional cation‐π biocatalysis, reported here is the anion‐π‐catalyzed epoxide‐opening ether cyclizations of oligomers. Only on π‐acidic aromatic surfaces having a positive quadrupole moment, such as hexafluorobenzene to naphthalenediimides, do these polyether cascade cyclizations proceed with exceptionally high autocatalysis (rate enhancements k_auto/k_cat >10⁴ m ^?1). This distinctive characteristic adds complexity to reaction mechanisms (Goldilocks‐type substrate concentration dependence, entropy‐centered substrate destabilization) and opens intriguing perspectives for future developments.     

Enantioselective Total Synthesis of (+)‐Plumisclerin A

The first and enantioselective total synthesis of (+)‐plumisclerin A, a novel unique complex cytotoxic marine diterpenoid, has been accomplished. Around the central cyclopentane anchorage, a sequential ring‐formation protocol was adopted to generate the characteristic tricycle[4.3.1.0^1,5]decane and trans‐fused dihyrdopyran moiety. Scalable enantioselective La^III‐catalyzed Michael reaction, palladium(0)‐catalyzed carbonylation and SmI₂‐mediated radical conjugate addition were successfully applied in the synthesis, affording multiple grams of the complex and rigid B/C/D‐ring system having six continuous stereogenic centers and two all‐carbon quaternary centers. The trans‐fused dihyrdopyran moiety with an exo side‐chain was furnished in final stage through sequential redox transformations from a lactone precursor, which overcome the largish steric strain of the dense multiring system. The reported total synthesis also confirms the absolute chemistries of natural (+)‐plumisclerin A.