Shimalactone Biosynthesis Involves Spontaneous Double Bicyclo-Ring Formation with 8π-6π Electrocyclization

Shimalactones A and B are neuritogenic polyketides possessing characteristic oxabicyclo[2.2.1]heptane and bicyclo[4.2.0]octadiene ring systems that are produced by the marine fungus Emericella variecolor GF10. We identified a candidate biosynthetic gene cluster and conducted heterologous expression analysis. Expression of ShmA polyketide synthase in Aspergillus oryzae resulted in the production of preshimalactone. Aspergillus oryzae and Saccharomyces cerevisiae transformants expressing ShmA and ShmB produced shimalactones A and B, thus suggesting that the double bicyclo-ring formation reactions proceed non-enzymatically from preshimalactone epoxide. DFT calculations strongly support the idea that oxabicyclo-ring formation and 8π-6π electrocyclization proceed spontaneously after opening of the preshimalactone epoxide ring through protonation. We confirmed the formation of preshimalactone epoxide in vitro, followed by its non-enzymatic conversion to shimalactones in the dark.     

Pd‐Catalyzed Cycloisomerization of 4‐Aza‐1,6‐enynes to 3‐Aza‐bicyclo[4.1.0]hept‐2‐enes

A method for the synthesis of bicyclo[4.1.0]heptenes from 1,6‐enynes through Pd‐catalyzed cycloisomerization has been developed. N‐ and O‐tethered 1,6‐enynes were successfully transformed to their corresponding 3‐aza‐ and 3‐oxabicyclo[4.1.0]heptenes in reasonable‐to‐high yields using the catalysts [PdCl₂(CH₃CN)₂]/P(OPh)₃ or [Pd(maleimidate)₂(PPh₃)₂] in toluene. The computational calculations using density functional theory indicate that [PdCl₂{P(OPh)₃}] in the oxidation state Pd^II acts as the active catalyst species for the formation of 3‐azabicyclo[4.1.0]heptenes through 6‐endo‐dig cyclization.     

On the π‐Electron Distribution in Biphenylene Analogues

The bonding situation in a series of biphenylene analogues – benzo[b]biphenylene and its dication, 4,10‐dibromobenzo[b]biphenylene, naphtho[2,3‐b]biphenylene and its dianion, benzo[a]biphenylene, (biphenylene)tricarbonylchromium, benzo[3,4]cyclobuta[1,2‐c]thiophene, benzo[3,4]cyclobuta[1,2‐c]thiophene 2‐oxide, benzo[3,4]cyclobuta[1,2‐c]thiophene 2,2‐dioxide, 4,10‐diazabenzo[b]biphenylene, biphenylene‐2,3‐dione, benzo[3,4]cyclobuta[1,2‐b]anthracene‐6,11‐dione, and 3,4‐dihydro‐2H‐benzo[3,4]cyclobuta[1,2]cycloheptene – where one of the two benzo rings of biphenylene is replaced by a different π‐system (B) was investigated on the basis of the NMR parameters of these systems. From the vicinal ¹H,¹H spin‐spin coupling constants, the electronic structure of the remaining benzo ring (A) is derived via the Q‐value method. It is found that increasing tendency of B to tolerate exocyclic double bonds at the central four‐membered ring of these systems favors increased π‐electron delocalization in the A ring. The analysis of the chemical shifts supports this conclusion. NICS (nucleus‐independent chemical shift) values as well as C,C bond lengths derived from ab initio calculations are in excellent agreement with the experimental data. The charged systems benzo[b]biphenylene dication and naphtho[2,3‐b]biphenylene dianion ( 7 ²⁻) are also studied by ¹³C NMR measurements. The charge distribution found closely resembles the predictions of the simple HMO model and reveals that 7 ²⁻ can be regarded as a benzo[3,4]cyclobuta[1,2‐b]‐substituted anthracene dianion. It is shown that the orientation of the tricarbonylchromium group in complexes of benzenoid aromatics can be derived from the vicinal ¹H,¹H coupling constants.     

Water‐Soluble Non‐Classical Benzene Mimetics

A new generation of saturated benzene mimetics, 2‐oxabicyclo[2.1.1]hexanes, was developed. These compounds were designed as analogues of bicyclo[1.1.1]pentane with an improved water solubility. Crystallographic analysis of 2‐oxabicyclo[2.1.1]hexanes revealed that they occupy a novel chemical space, but, at the same time, resemble the motif of meta‐disubstituted benzenes.     

Synthesis of the Chiral Pair of a Novel Thromboxane Antagonist, 3‐[2‐(3‐Benzenesulfonylamino‐7‐oxabicyclo[2.2.1]hept‐2‐yl‐methyl)phenyl] Propionic Acid

Preparation of the enantiomeric pair of 3‐[2‐(3‐benzenesulfonylamino‐7‐oxabicyclo[2.2.1]hept‐2‐yl‐methyl)phenyl] propionic acid, a novel thromboxane antagonist is reported. They are synthesized from either enantiomers of known (1R,2R,3R,4S)‐3‐[2‐(3‐carboxy‐7‐oxabicyclo[2,2,1]hept‐2‐yl‐methyl)phenyl]‐propionic acid methyl ester via epimerization, modified Curtius' rearrangement and sulfonylamino formation. Other derivatives may be prepared similarly.     

A novel route to bicyclic iron tricarbonyl complexes involving π-allyl and σ-components

Nucleophilic attack of CN⁻ on bicyclo[3.2.1]octadienyl-, bicyclo[3.2.2]- nonadienyl-, and 6,7-benzobicyclo[3.2.2]nonadienyliron tricarbonyl tetrafluoroborates, results in mixed-type complexes containing both σ and π-allyl bonds. The cyano group in the products is located exo to the bicyclic ring.In contrast, the three cations react smoothly with I⁻; carbon monoxide is displaced to give iron complexes containing covalently-bound halogen.     

Concise Synthesis of 3D π‐Extended Polyphenylene Cylinders

The synthesis of structurally well‐defined, monodisperse carbon nanotube (CNT) sidewall segments poses a challenge in materials science. The synthesis of polyphenylene cylinders that comprise typical benzene connectivity to resemble precursors of [9,9] and [15,15] CNTs is now reported, and the products were characterized by X‐ray crystallography. To investigate the oxidative cyclodehydrogenation of ring‐strained molecules as a final step towards a bottom‐up synthesis of CNT sidewall segments, phenylene‐extended cyclic p‐hexaphenylbenzene trimers ([3]CHPB) were prepared, and NMR studies revealed a strain‐induced 1,2‐phenyl shift. It was further shown that an increase in ring size leads to selectively dehydrogenated macrocycles. Larger homologues are envisioned to give smooth condensation reactions toward graphenic sidewalls and should be used in the future as seeds for CNT formation.     

Arginine‐Facilitated α‐ and π‐Radical Migrations in Glycylarginyltryptophan Radical Cations

We have used model tripeptides GXW (with X being one of the amino acid residues glycine (G), alanine (A), leucine (L), phenylalanine (F), glutamic acid (E), histidine (H), lysine (K), or arginine (R)) to study the effects of the basicity of the amino acid residue on the radical migrations and dissociations of odd‐electron molecular peptide radical cations M^.+ in the gas phase. Low‐energy collision‐induced dissociation (CID) experiments revealed that the interconvertibility of the isomers [G^.XW]⁺ (radical centered on the N‐terminal α‐carbon atom) and [GXW]^.+ (radical centered on the π system of the indolyl ring) generally increased upon increasing the proton affinity of residue X. When X was arginine, the most basic amino acid, the two isomers were fully interconvertible and produced almost identical CID spectra despite the different locations of their initial radical sites. The presence of the very basic arginine residue allowed radical migrations to proceed readily among the [G^.RW]⁺ and [GRW]^.+ isomers prior to their dissociations. Density functional theory calculations revealed that the energy barriers for isomerizations among the α‐carbon‐centered radical [G^.RW]⁺, the π‐centered radical [GRW]^.+, and the β‐carbon‐centered radical [GRW_β^.]⁺ (ca. 32–36 kcal mol⁻¹) were comparable with those for their dissociations (ca. 32–34 kcal mol⁻¹). The arginine residue in these GRW radical cations tightly sequesters the proton, thereby resulting in minimal changes in the chemical environment during the radical migrations, in contrast to the situation for the analogous GGW system, in which the proton is inefficiently stabilized during the course of radical migration.     

Phosphorescence Resulting from Interaction between Two Non‐equivalent Metals on a Helical π‐Conjugated Surface

A [7]helicene bis‐ruthenium complex, with one ruthenium atom bound to the cyclopentadienyl (Cp) ring and the other coordinated to the arene ring at the edge of the helicene, was synthesized. This complex showed phosphorescence both in butyronitrile (Φ=31 %, 77 K) and in the solid state (Φ=18 %, 77 K). The two non‐equivalent ruthenium metal atoms, attached to the helicene ligand, interact with each other upon photoabsorption and emission.     

Primary Anion–π Catalysis of Epoxide‐Opening Ether Cyclization into Rings of Different Sizes: Access to New Reactivity

The concept of anion–π catalysis focuses on the stabilization of anionic transition states on aromatic π surfaces. Recently, we demonstrated the occurrence of epoxide‐opening ether cyclizations on aromatic π surfaces. Although the reaction proceeded through unconventional mechanisms, the obtained products are the same as those from conventional Brønsted acid catalysis, and in agreement with the Baldwin selectivity rules. Different mechanisms, however, should ultimately lead to new products, a promise anion–π catalysis has been reluctant to live up to. Herein, we report non‐trivial reactions that work with anion–π catalysis, but not with Brønsted acids, under comparable conditions. Namely, we show that the anion–π templated autocatalysis and epoxide opening with alcoholate–π interactions can provide access to unconventional ring chemistry. For smaller rings, anion–π catalysis affords anti‐Baldwin oxolanes, 2‐oxabicyclo[3.3.0]octanes, and the expansion of Baldwin oxetanes by methyl migration. For larger rings, anion–π templated autocatalysis is thought to alleviate the entropic penalty of folding to enable disfavored anti‐Baldwin cyclizations into oxepanes and oxocanes.     

Synthesis of some fused β‐carbolines including the first example of the pyrrolo[3,2‐c]‐β‐carboline system

Condensation of 1‐methyl‐β‐carboline‐3‐carbaldehyde with ethyl azidoacetate and subsequent thermolysis of the resulting azidopropenoate was used to [c] annulate a pyrrole ring onto the β‐carboline moiety, thus producing the first example of the pyrrolo[3,2‐c]‐β‐carboline ring system. The latter ring system results from cyclization at the C‐4 carbon, whereas cyclization at the N‐2 nitrogen atom also occurs to form a pyrazolo[3,2‐c]‐β‐carboline ring system. Condensation of β‐carboline‐1‐carbaldehyde with ethyl azidoacetate produced a non‐isolable intermediate, which immediately underwent cyclization, however in this case cyclization occurred via attack at the ester and the azide remained intact. The resulting 5‐azidocanthin‐6‐one was transformed to the first examples of 5‐aminocanthin‐6‐ones. β‐Carboline‐1,3‐dicarbaldehyde failed to give an acceptable reaction with ethyl azidoacetate, but did undergo selective condensation with dimethyl acetylene dicarboxylate at the C‐1 carbaldehyde with concomitant cyclization to form a highly functionalized 2‐formyl‐canthine derivative.     

Light‐Induced Cycloaddition of 2,3‐Dihydro‐2,2‐dimethyl‐4H‐thiopyran‐4‐one (a 4‐Thiacyclohex‐2‐enone) to Alkenes and Dienes

The reactivity of (thiacyclic)‐2,3‐dihydro‐2,2‐dimethyl‐4H‐thiopyran‐4‐one ( 1a ) in light‐induced cycloadditions to furan ( F ), acrylonitrile ( AN ), or 2,3‐dimethylbut‐2‐ene ( TME ) is compared to that of (carbocyclic) 5,5‐dimethylcyclohex‐2‐enone ( 1b ). Whereas for the more‐flexible thiacycle, the efficiency of [2+2]‐photocycloadduct formation with AN or TME is generally much lower, the diastereoselectivity regarding the ring fusion in the bicyclo[4.2.0]octanes is quite similar for both enones. In contrast, 1a affords exclusively trans‐fused [4+2] cycloadducts with F , while 1b gives predominantly the corresponding cis‐fused products.     

Phosphate‐Tether‐Mediated Ring‐Closing Metathesis for the Preparation of Complex 1,3‐anti‐Diol‐Containing Subunits

An array of examples of diastereoselective, phosphate‐tether‐mediated ring‐closing metathesis reactions, which highlight the importance of product ring size and substrate stereochemical compatibility, as well as complexity, is reported. Studies focus primarily on the formation of bicyclo[n.3.1]phosphates, involving the coupling of C₂‐symmetric dienediol subunits with a variety of simple, as well as complex, alcohol partners.     

Photocycloaddition of Cyclohex‐2‐enones to 2‐Methylbut‐1‐en‐3‐yne

Irradiation (350 nm) of 2‐alkynylcyclohex‐2‐enones 1 in benzene in the presence of an excess of 2‐methylbut‐1‐en‐3‐yne ( 2 ) affords in each case a mixture of a cis‐fused 3,4,4a,5,6,8a‐hexahydronaphthalen‐1(2H)‐one 3 and a bicyclo[4.2.0]octan‐2‐one 4 (Scheme 2), the former being formed as main product via 1,6‐cyclization of the common biradical intermediate. The (parent) cyclohex‐2‐enone and other alkylcyclohex‐2‐enones 7 also give naphthalenones 8 , albeit in lower yields, the major products being bicyclo[4.2.0]octan‐2‐ones (Scheme 4). No product derived from such a 1,6‐cyclization is observed in the irradiation of 3‐alkynylcyclohex‐2‐enone 9 in the presence of 2 (Scheme 4). Irradiation of the 2‐cyano‐substituted cyclohexenone 12 under these conditions again affords only traces of naphthalenone 13 , the main product now being the substituted bicyclo[4.2.0]oct‐7‐ene 16 (Scheme 5), resulting from [2+2] cycloaddition of the acetylenic C−C bond of 2 to excited 12 .     

Tuning the π‐π stacking distance and J‐aggregation of DPP‐based conjugated polymer via introducing insulating polymer

The close π–π stacking and the high J‐aggregation during the formation of fibrillar morphology in films of the poly[[2,5‐bis(2‐octyldodecyl)?2,3,5,6‐tetrahydro‐3,6‐dioxopyrrolo[3,4‐c]pyrrole‐1,4‐diyl]‐alt–[[2,2′‐(2,5‐thiophene)bis‐thieno[3,2‐b]thiophen]‐5,5′‐diyl]] (PDPPTT‐T) are demonstrated via blending with polystyrene (PS). The hydrodynamic radius (R_h) of PDPPTT‐T is decreased from 16.7 nm in the neat solution to 12.7 nm in the blend solution at the ratio of 1/20(PDPPTT‐T/PS). This phenomenon suggests that blending PS is beneficial for the disentanglement of PDPPTT‐T. The disentanglement of PDPPTT‐T facilitates the formation of fibrillar morphology. The growth of the fibrils occurs along the molecular backbones and the width of the fibrils is parallel to the π–π stacking direction. The disentanglement of PDPPTT‐T helps the molecules adjust conformation to improve J‐aggregation and decrease the π–π stacking distance. The maximum absorption is red‐shifted from 825 nm to 849 nm and the relative intensity of J‐aggregation (the 0‐0/0‐1 ratio) is increased from 1.19 to 1.60. The π–π stacking distance decreases from 3.57 to 3.52 Å. The charge‐carrier mobility will be improved in the fibrillar morphology with close π–π stacking and high J‐aggregation. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part B: Polym. Phys. 2016 , 54, 838–847     

Stereoselective Synthesis of Tropanes via a 6π‐Electrocyclic Ring‐Opening/ Huisgen [3+2]‐Cycloaddition Cascade of Monocyclopropanated Heterocycles

The synthesis of tropanes via a microwave‐assisted, stereoselective 6π‐electrocyclic ring‐opening/ Huisgen [3+2]‐cycloaddition cascade of cyclopropanated pyrrole and furan derivatives with electron‐deficient dipolarophiles is demonstrated. Starting from furans or pyrroles, 8‐aza‐ and 8‐oxabicyclo[3.2.1]octanes are accessible in two steps in dia‐ and enantioselective pure form, being versatile building blocks for the synthesis of pharmaceutically relevant targets, especially for new cocaine analogues bearing various substituents at the C‐6/C‐7 positions of the tropane ring system. Moreover, the 2‐azabicyclo[2.2.2]octane core (isoquinuclidines), being prominently represented in many natural and pharmaceutical products, is accessible via this approach.     

Rapid Access to Oxabicyclo[2.2.2]octane Skeleton through Cu(I)‐Catalyzed Generation and Trapping of Vinyl‐o‐quinodimethanes (Vinyl‐o‐QDMs)†

A Cu(I)‐catalyzed three‐component reaction of terminal enynals/enynones, diazo compounds, and alkenes has been developed. With this method, a series of oxabicyclo[2.2.2]octanes were effectively synthesized in high yields under mild reaction conditions. This transformation is proposed to proceed through trapping of the cyclic vinyl‐o‐quinodimethanes (vinyl‐o‐QDMs) species, which were generated from terminal enynals/enynones and diazo compounds by alkenes. The obvious advantages of wide substrate scopes, mild reaction conditions, and high seteroselectivity and atom efficiency make this reaction highly appealing for construction of highly rigid [2.2.2]octane skeleton.     

Stereoselective Synthesis of 8‐Oxabicyclo[3.2.1]octane‐2,3,4,6,7‐pentols and Total Asymmetric Synthesis of 2,6‐Anhydrohepturonic Acid Derivatives and of β‐C‐manno‐Pyranosides Suitable for the Construction of (1→3)‐C,C‐Linked Trisaccharides

Enantiomerically pure (+)‐(1S,4S,5S,6S)‐6‐endo‐(benzyloxy)‐5‐exo‐{[(tert‐butyl)dimethylsilyl]oxy}‐7‐oxabicyclo[2.2.1]heptan‐2‐one ((+)‐ 5 ) and its enantiomer (−)‐ 5 , obtained readily from the Diels‐Alder addition of furan to 1‐cyanovinyl acetate, can be converted with high stereoselectivity into 8‐oxabicyclo[3.2.1]octane‐2,3,4,6,7‐pentol derivatives (see 23 – 28 in Scheme 2). A precursor of them, (1R,2S,4R,5S,6S,7R,8R)‐7‐endo‐(benzyloxy)‐8‐exo‐hydroxy‐3,9‐dioxatricyclo[4.2.1.0^2,4]non‐5‐endo‐yl benzoate ((−)‐ 19 ), is transformed into (1R,2R,5S, 6S,7R,8S)‐6‐exo,8‐endo‐bis(acetyloxy)‐2‐endo‐(benzyloxy)‐4‐oxo‐3,9‐dioxabicyclo[3.3.1]non‐7‐endo‐yl benzoate ((−)‐ 43 ) (see Scheme 5). The latter is the precursor of several protected 2,6‐anhydrohepturonic acid derivatives such as the diethyl dithioacetal (−)‐ 57 of methyl 3,5‐di‐O‐acetyl‐2,6‐anhydro‐4‐O‐benzoyl‐D ‐glycero‐D ‐galacto‐hepturonate (see Schemes 7 and 8). Hydrolysis of (−)‐ 57 provides methyl 3,5‐di‐O‐acetyl‐2,6‐anhydro‐4‐O‐benzoyl‐D ‐glycero‐D ‐galacto‐hepturonate 48 that undergoes highly diastereoselective Nozaki‐Oshima condensation with the aluminium enolate resulting from the conjugate addition of Me₂AlSPh to (1S,5S,6S,7S)‐7‐endo‐(benzyloxy)‐6‐exo‐{[(tert‐butyl)dimethylsilyl]oxy}‐8‐oxabicyclo[3.2.1]oct‐3‐en‐2‐one ((−)‐ 13 ) derived from (+)‐ 5 (Scheme 12). This generates a β‐C‐mannopyranoside, i.e., methyl (7S)‐3,5‐di‐O‐acetyl‐2,6‐anhydro‐4‐O‐benzoyl‐7‐C‐[(1R,2S,3R,4S,5R,6S,7R)‐6‐endo‐(benzyloxy)‐7‐exo‐{[(tert‐butyl)dimethylsilyl]oxy}‐4‐endo‐hydroxy‐2‐exo‐(phenylthio)‐8‐oxabicyclo[3.2.1]oct‐3‐endo‐yl]‐L ‐glycero‐D ‐manno‐heptonate ((−)‐ 70 ; see Scheme 12), that is converted into the diethyl dithioacetal (−)‐ 75 of methyl 3‐O‐acetyl‐2,6‐anhydro‐4,5‐dideoxy‐4‐C‐{[methyl (7S)‐3,5,7‐tri‐O‐acetyl‐2,6‐anhydro‐4‐O‐benzoyl‐L ‐glycero‐D ‐manno‐heptonate]‐7‐C‐yl}‐5‐C‐(phenylsulfonyl)‐L ‐glycero‐D ‐galacto‐hepturonate ( 76 ; see Scheme 13). Repeating the Nozaki‐Oshima condensation to enone (−)‐ 13 and the aldehyde resulting from hydrolysis of (−)‐ 75 , a (1→3)‐C,C‐linked trisaccharide precursor (−)‐ 77 is obtained.     

Donor–acceptor‐integrated conjugated polymers based on carbazole[3,4‐c:5,6‐c]bis[1,2,5]thiadiazole with tight π–π stacking for photovoltaics

An original strategy to construct a new donor–acceptor (D–A)‐integrated structure by directly imposing “pull” unit on the “push” moiety to form fused ring architecture has been developed, and poly{N‐alkyl‐carbazole[3,4‐c:5,6‐c]bis[1,2,5]thiadiazole‐alt‐thiophene} (PCBTT) with D–A‐integrated structure, in which two 1,2,5‐thiadiazole rings are fixed on carbazole in 3‐, 4‐ and 5‐, 6‐position symmetrically and thiophene is used as bridge, has been synthesized. The interaction between pull and push units has fine tuned the HOMO/LUMO energy levels, and the resulting copolymer covers the solar flux from 300 to 750 nm. The interaction between pull and push units is worth noting that due to the fused five rings inducing strong intermolecular interaction, an extremely short π–π stacking distance of 0.32 nm has been achieved for PCBTT both in powder and solid states. This is the shortest π–π stacking distance reported for conjugated polymers. Additionally, an obvious intramolecular charge transfer and energy transfer from donor units to acceptor units have been detected in this D–A integration. A moderate‐to‐high open‐circuit voltage of ～0.7 V in PCBTT:[6,6]‐phenyl‐C61 butyric acid methyl ester (PCBM) (w/w = 1/2) solar cells is achieved due to the low‐lying HOMO energy level of PCBTT. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2013     

A Unified Approach to the Daucane and Sphenolobane Bicyclo[5.3.0]decane Core: Enantioselective Total Syntheses of Daucene,Daucenal, Epoxydaucenal B,and 14‐para‐Anisoyloxydauc‐4,8‐diene

Access to the bicyclo[5.3.0]decane core found in the daucane and sphenolobane terpenoids via a key enone intermediate enables the enantioselective total syntheses of daucene, daucenal, epoxydaucenal B, and 14‐para‐anisoyloxydauc‐4,8‐diene. Central aspects include a catalytic asymmetric alkylation followed by a ring contraction and ring‐closing metathesis to generate the five‐ and seven‐membered rings, respectively.