DFT Study of a 5‐endo‐trig‐Type Cyclization of 3‐Alkenoic Acids by Using Pd–Spiro‐bis(isoxazoline) as Catalyst: Importance of the Rigid Spiro Framework for Both Selectivity and Reactivity

The reaction pathway of an enantioselective 5‐endo‐trig‐type cyclization of 3‐alkenoic acids catalyzed by a chiral palladium–spiro‐bis(isoxazoline) complex, Pd–SPRIX, has been studied by density functional theory calculations. The most plausible pathway involves intramolecular nucleophilic attack of the carboxylate moiety on the C?C double bond activated by Pd–SPRIX and β‐H elimination from the resulting organopalladium intermediate. The enantioselectivity was determined in the cyclization step through the formation of a π‐olefin complex, in which one of the two enantiofaces of the olefin moiety was selected. The β‐H elimination occurs via a seven‐membered cyclic structure in which the acetate ligand plays a key role in lowering the activation barrier of the transition state. In the elimination step, the SPRIX ligand was found to behave as a monodentate ligand due to the hemilability of one of the isoxazoline units thereby facilitating the elimination. Natural population analysis of this pathway showed that the more weakly electron‐donating SPRIX ligand, compared with the bis(oxazoline) ligand, BOX, facilitated the formation of the π‐olefin complex intermediate, leading to a smaller overall activation energy and a higher reactivity of the Pd–SPRIX catalyst.     

Enantioselective Radical‐Polar Crossover Reactions of Indanonecarboxamides with Alkenes

Highly efficient asymmetric intermolecular radical‐polar crossover reactions were realized by combining a chiral N,N′‐dioxide/Ni^II complex catalyst with Ag₂O under mild reaction conditions. Various terminal alkenes and indanonecarboxamides/esters underwent radical addition/cyclization reactions to afford spiro‐iminolactones and spirolactones with good to excellent yields (up to 99 %) and enantioselectivities (up to 97 % ee). Furthermore, a range of different radical‐mediated oxidation/elimination or epoxide ring‐opening products were obtained under mild reaction conditions. The Lewis acid catalysts exhibited excellent performance and precluded the strong background reaction.     

One‐Pot,Four‐Component Synthesis of Novel Spiro[indeno[2,1‐b]quinoxaline‐11,4′‐pyran]‐2′‐amines

A one‐pot, four‐component reaction for the efficient synthesis of novel spiro[indeno[2,1‐b]quinoxaline‐11,4′‐pyran]‐2′‐amines by using InCl₃ is described. The syntheses are achieved by reacting ninhydrin with 1,2‐diaminobenzenes to give indenoquinoxalines, which are trapped in situ by alkyl malonates and various α‐methylencarbonyl compounds through cyclization, providing multifunctionalized spiro‐substituted indeno[2,1‐b]quinoxaline‐11,4′‐pyran‐2′‐amines.     

Simplified synthesis of spiro‐bridged ladder‐type poly(p‐phenylene)

In this study, a simplified route to synthesize soluble, spiro‐bridged ladder‐type poly(p‐phenylene)s (spiro‐LPPP) was developed. The new, simplified synthesis route for spiro‐LPPP involves two reaction steps: a single‐stranded precursor polymer containing diaryloylbenzene building blocks was obtained by the Suzuki reaction, followed by a subsequent twofold cyclization cascade using methanesulfonic acid to form the target spiro‐LPPP. Spiro‐LPPP shows a well‐defined chemical structure, high molecular weight (M_n of 17,500 g/mol with a polydispersity index of 2.0), excellent thermal stability (5% weight loss at 370 °C), and good solubility in common organic solvents. Spiro‐LPPP emits blue light (λ_max,em = 455 nm) with the high solution PL quantum yield (94%). The spectral properties of spiro‐LPPP in the solid state are very similar to the solution properties, thus indicating a low degree of intermolecular aggregation. After annealing a thin film of spiro‐LPPP to 120 °C in air for 3 to 24 h, its emission spectrum is unchanged, reflecting excellent thermooxidative stability. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 5137–5143, 2009     

(+)‐Geodin from Aspergillus terreus

The fungal metabolite (+)‐geodin [systematic name: (2R)‐methyl 5,7‐dichloro‐4‐hydroxy‐6′‐methoxy‐6‐methyl‐3,4′‐dioxospiro[benzofuran‐2,1′‐cyclohexa‐2′,5′‐diene]‐2′‐carboxylate], C₁₇H₁₂Cl₂O₇, was isolated from Aspergillus terreus. The crystal structure contains two independent molecules in the asymmetric unit. Molecules denoted 1 interact through O—H...O hydrogen bonds creating chains of molecules parallel to the crystallographic 2₁ screw axis. Molecules denoted 2 interact through an O...Cl halogen bond, also creating chains of molecules parallel to the crystallographic 2₁ screw axis. Molecules 1 and 2 interact through another O...Cl halogen bond. The two molecules are similar but molecules 2 have a slightly more planar cyclohexadiene ring than molecules 1. The absolute structure of (+)‐geodin has been unequivocally assigned with the spiro centre having the R configuration in both molecules. The structurally related (+)‐griseofulvin has an S configuration at the spiro centre, a difference of potential biological and biosynthetic relevance.     

Efficient Access to Bicyclo[4.3.0]nonanes: Copper‐Catalyzed Asymmetric Silylative Cyclization of Cyclohexadienone‐Tethered Allenes

The creation of three consecutive chiral carbon centers in one step is achieved using Cu‐catalyzed asymmetric silylative cyclization of cyclohexadienone‐tethered allenes. Through regioselective β‐silylation of the allene and subsequent enantioselective 1,4‐addition to cyclohexadienone, this tandem reaction could afford cis‐hydrobenzofuran, cis‐hydroindole, and cis‐hydroindene frameworks with excellent yields (80–98 %) and enantioselectivities (94–98 % ee) bearing vinylsilane and enone substructures. Meanwhile, this mild transformation is generally compatible with a wide range of functional groups, which allows further conversion of the bicyclic products to bridged and tricyclic ring structures.     

Mechanism of the Transition‐Metal‐Catalyzed Hydroarylation of Bromo‐Alkynes Revisited: Hydrogen versus Bromine Migration

A comprehensive mechanistic study of the InCl₃‐, AuCl‐, and PtCl₂‐catalyzed cycloisomerization of the 2‐(haloethynyl)biphenyl derivatives of Fürstner et al. was carried out by DFT/M06 calculations to uncover the catalyst‐dependent selectivity of the reactions. The results revealed that the 6‐endo‐dig cyclization is the most favorable pathway in both InCl₃‐ and AuCl‐catalyzed reactions. When AuCl is used, the 9‐bromophenanthrene product could be formed by consecutive 1,2‐H/1,2‐Br migrations from the Wheland‐type intermediate of the 6‐endo‐dig cyclization. However, in the InCl₃‐catalyzed reactions, the chloride‐assisted intermolecular H‐migrations between two Wheland‐type intermediates are more favorable. These Cl‐assisted H‐migrations would eventually lead to 10‐bromophenanthrene through proto‐demetalation of the aryl indium intermediate with HCl. The cause of the poor selectivity of the PtCl₂ catalyst in the experiments by the Fürstner group was predicted. It was found that both the PtCl₂‐catalyzed alkyne–vinylidene rearrangement and the 5‐exo‐dig cyclization pathways have very close activation energies. Further calculations found the former pathway would lead eventually to both 9‐ and 10‐bromophenanthrene products, as a result of the Cl‐assisted H‐migrations after the cyclization of the Pt–vinylidene intermediate. Alternatively, the intermediate from the 5‐exo‐dig cyclization would be transformed into a relatively stable Pt–carbene intermediate irreversibly, which could give rise to the 9‐alkylidene fluorene product through a 1,2‐H shift with a 28.1 kcal mol^?1 activation barrier. These findings shed new light on the complex product mixtures of the PtCl₂‐catalyzed reaction.     

Three‐Component Reaction for Construction of Spiro[indoline‐3,7′‐thiazolo[3,2‐a]pyridines] and Spiro[benzo[4,5]thiazolo[3,2‐a]pyridine‐3,3′‐indolines]

The three‐component reaction of thiazole (benzothiazole), dialkyl but‐2‐ynedioate, and isatinylidene malononitriles in toluene at 110–120°C in a sealed tube afforded a mixture of cis/trans‐isomers of functionalized diastereoisomeric spiro[indoline‐3,7′‐thiazolo[3,2‐a]pyridines] and spiro[benzo[4,5]thiazolo[3,2‐a]pyridine‐3,3′‐indolines] in good yields. Both cis‐isomers and trans‐isomers were successfully separated out and fully characterized with spectroscopy and single crystal determination. Under similar conditions, the three‐component reaction containing 2‐(1,3‐dioxo‐1H‐inden‐2(3H)‐ylidene)malononitrile resulted in spiro[indene‐2,7′‐thiazolo[3,2‐a]pyridine] derivatives.     

Two regioisomers of condensed thioheterocyclic triazine synthesized from 6‐phenyl‐3‐thioxo‐2,3,4,5‐tetrahydro‐1,2,4‐triazin‐5‐one

In the crystal structure of 6‐phenyl‐3‐thioxo‐2,3,4,5‐tetrahydro‐1,2,4‐triazin‐5‐one, C₉H₇N₃OS, (I), the 1,2,4‐triazine moieties are connected by face‐to‐face contacts through two kinds of double hydrogen bonds (N—H...O and N—H...S), which form planar ribbons along the a axis. The ribbons are crosslinked through C—H...π interactions between the phenyl rings. The molecular structures of two regioisomeric compounds, namely 6‐phenyl‐2,3‐dihydro‐7H‐1,3‐thiazolo[3,2‐b][1,2,4]triazin‐7‐one, C₁₁H₉N₃OS, (II), and 3‐phenyl‐6,7‐dihydro‐4H‐1,3‐thiazolo[2,3‐c][1,2,4]triazin‐4‐one, C₁₁H₉N₃OS, (III), which were prepared by the condensation reaction of (I) with 1,2‐dibromoethane, have been characterized by X‐ray crystallography and spectroscopic studies. The crystal structures of (II) and (III) both show two crystallographically independent molecules. While the two compounds are isomers, the unit‐cell parameters and crystal packing are quite different and (II) has a chiral crystal structure.     

Asymmetric Synthesis and Antitumor Activity of Spiro‐Oxadiazole Derivatives from 1,4:3,6‐Dianhydro‐D‐fructose

A series of spiro‐oxadiazoles were synthesized from 1,4:3,6‐dianhydro‐D ‐fructose and hydrazides via a stereo‐ selective two‐step reaction sequence. The structures of newly synthesized compounds were established by spectral analysis. The absolute configuration of compound 2a was further confirmed by single crystal X‐ray analysis. All the synthesized compounds were screened for their in vitro antitumor activity, showing that these compounds have poor inhibitory activities against A549, MGC‐803 tumor cells.     

Ring opening of pyridines: the pseudo‐cis and pseudo‐trans isomers of tetra‐n‐butylammonium 4‐nitro‐5‐oxo‐2‐pentenenitrilate

The reaction of 2‐chloro‐5‐nitropyridine with two equivalents of base produces the title carbanion as an intermediate in a ring‐opening/ring‐closing reaction. The crystal structures of the tetra‐n‐butylammonium salts of the intermediates, C₁₆H₃₆N⁺·C₅H₃N₂O₃⁻, revealed that pseudo‐cis and pseudo‐trans isomers are possible. One crystal structure displayed a mixture of the two isomers with approximately 90% pseudo‐cis geometry and confirms the structure predicted by the S_N(ANRORC) mechanism. The pseudo‐cis intermediate undergoes a slow isomerization over a period of months to the pseudo‐trans isomer, which does not have the appropriate geometry for the subsequent ring‐closing reaction. The structure of the pure pseudo‐trans isomer is also reported. In both isomers, the negative charge is highly delocalized, but relatively small differences in C—C bond distances indicate a system of conjugated double bonds with the nitro group bearing the negative charge. The packing of the two unit cells is very similar and largely determined by the interactions between the planar carbanion and the bulky tetrahedral cation.     

Stereospecific and Chemoselective Copper‐Catalyzed Deaminative Silylation of Benzylic Ammonium Triflates

A method for the synthesis of benzylsilanes starting from the corresponding ammonium triflates is reported. Silyl boronic esters are employed as silicon pronucleophiles, and the reaction is catalyzed by copper(I) salts. Enantioenriched benzylic ammonium salts react stereospecifically through an S_N2‐type displacement of the ammonium group to afford α‐chiral silanes with inversion of the configuration. A cyclopropyl‐substituted substrate does not undergo ring opening, thus suggesting an ionic reaction mechanism with no benzyl radical intermediate.     

Tribenzotriquinacenes Based on Regioselective Bis‐formylation: Optical Resolution and Absolute Configuration of Inherently Chiral Derivatives and Synthesis of the First Cyclophane‐Type Tribenzotriquinacene Dimers

Enantiomerically pure tribenzotriquinacenes (TBTQs) bearing two monofunctionalized aromatic nuclei were synthesized for the first time and their optical properties and absolute configuration determined. A remarkably regioselective bis‐formylation of the fully bridgehead methylated parent TBTQ hydrocarbon with MeOCHCl₂/TiCl₄ afforded a mixture of two C_s‐symmetrical (achiral) difunctionalized derivatives together with one C₁‐symmetrical (chiral) isomer. Reduction and subsequent column chromatography furnished the three respective benzylic TBTQ dialcohols. Optical resolution of the racemic 2,6‐bis(hydroxymethyl) derivative was achieved via the diastereomeric (R)‐1,1′‐bi‐2‐naphthol ethers and the absolute configuration of the enantiomers was determined by CD exciton model analysis. The electronic circular dichroism (ECD) spectra and the specific rotation of the enantiomers were found to agree with the results of DFT calculations. Among the C_s‐symmetrical isomers, the “proximal” 2,11‐dialdehyde and the corresponding benzylic dialcohol were identified by 2D NMR spectroscopy and X‐ray crystallographic analysis, respectively, and used as the starting point for the synthesis of several novel dithiametacyclophanes. These include the first “dimeric” tribenzotriquinacene‐based cyclophanes bearing the bowls of the two TBTQ units attached to each other in a syn (concave–concave) or anti (convex–concave) configuration. The usefulness of such thiacyclophanes as fluorescent chemosensors for different metal ions is also demonstrated.     

A Visible Light Photocatalytic Cross‐Dehydrogenative Coupling/Dehydrogenation/6π‐Cyclization/Oxidation Cascade: Synthesis of 12‐Nitroindoloisoquinolines from 2‐Aryltetrahydroisoquinolines

A visible light‐induced photocatalytic dehydrogenation/6π‐cyclization/oxidation cascade converts 1‐(nitromethyl)‐2‐aryl‐1,2,3,4‐tetrahydroisoquinolines into novel 12‐nitro‐substituted tetracyclic indolo[2,1‐a]isoquinoline derivatives. Various photocatalysts promote the reaction in the presence of air and a base, the most efficient being 1‐aminoanthraquinone in combination with K₃PO₄. Further, the 12‐nitroindoloisoquinoline products can be accessed directly from C1‐unfunctionalized 2‐aryl‐1,2,3,4‐tetrahydroisoquinolines by extending the one‐pot protocol with a foregoing photocatalytic cross‐dehydrogenative coupling reaction, resulting in a quadruple cascade transformation.     

Total Synthesis of (−)‐Platensimycin by Advancing Oxocarbenium‐ and Iminium‐Mediated Catalytic Methods

(?)‐Platensimycin is a potent inhibitor of fatty acid synthase that holds promise in the treatment of metabolic disorders (e.g., diabetes and “fatty liver”) and pathogenic infections (e.g., those caused by drug‐resistant bacteria). Herein, we describe its total synthesis through a four‐step preparation of the aromatic amine fragment and an improved stereocontrolled assembly of the ketolide fragment, (?)‐platensic acid. Key synthetic advances include 1) a modified Lieben haloform reaction to directly convert an aryl methyl ketone into its methyl ester within 30 seconds, 2) an experimentally improved dialkylation protocol to form platensic acid, 3) a sterically controlled chemo‐ and diastereoselective organocatalytic conjugate reduction of a spiro‐cyclized cyclohexadienone by using the trifluoroacetic acid salt of α‐amino di‐tert‐butyl malonate, 4) a tetrabutylammonium fluoride promoted spiro‐alkylative para dearomatization of a free phenol to assemble the cagelike ketolide core with the moderate leaving‐group ability of an early tosylate intermediate, and 5) a bismuth(III)‐catalyzed Friedel–Crafts cyclization of a free lactol, with LiClO₄ as an additive to liberate a more active oxocarbenium perchlorate species and suppress the Lewis basicity of the sulfonyloxy group. The longest linear sequence is 21 steps with an overall yield of 3.8 % from commercially available eugenol.     

(1R,3R,4S)‐1‐Benzyl‐3‐(tert‐butyldimethylsilyloxy)‐4‐(hydroxymethyl)pyrrolidine–borane: novel B—H...H—O hydrogen bonding

The absolute configuration of the title cis‐(1R,3R,4S)‐pyrrolidine–borane complex, C₁₈H₃₄BNO₂Si, was confirmed. Together with the related trans isomers (3S,4S) and (3R,4R), it was obtained unexpectedly from the BH₃·SMe₂ reduction of the corresponding chiral (3R,4R)‐lactam precursor. The phenyl ring is disordered over two conformations in the ratio 0.65:0.35. The crystallographic packing is dominated by the rarely found donor–acceptor hydroxy–borane O—H...H—B hydrogen bonds.     

Two conformers of 10,11‐dihydro‐5H‐dibenzo[a,d]cyclo­heptene spiro‐linked with homobenzoquinone epoxide

The crystal structures of the two thermally equilibrated conformational isomers of the epoxide 1′,5′‐dimethyl­spiro[10,11‐dihydro‐5H‐dibenzo[a,d]cyclo­heptene‐5,8′‐4′‐oxatricyclo[5.1.0.0^3,5]octane]‐2′,6′‐dione, C₂₃H₂₀O₃, have been determined by X‐ray diffraction. In the tricyclic dione skeleton, the oxirane and cyclo­propane rings adopt an anti structure with respect to the conjunct quinone frame. The spiro‐linked 10,11‐dihydro‐5H‐dibenzo[a,d]cyclo­heptene ring of the major isomer has a fairly twisted boat form, folding opposite to the adjoining cyclo­propane methyl substituent, whereas the seven‐membered ring of the minor isomer has an almost ideal twist–boat form, inversely folding to the side of the relevant methyl group. The conformational structures of these isomers have been compared with those of the corresponding isomers of the unepoxidized homobenzoquinone.     

Gold(III) Chloride Catalyzed Synthesis of Chiral Substituted 3‐Formyl Furans from Carbohydrates: Application in the Synthesis of 1,5‐Dicarbonyl Derivatives and Furo[3,2‐c]pyridine

This report describes a gold(III)‐catalyzed efficient general route to densely substituted chiral 3‐formyl furans under extremely mild conditions from suitably protected 5‐(1‐alkynyl)‐2,3‐dihydropyran‐4‐one using H₂O as a nucleophile. The reaction proceeds through the initial formation of an activated alkyne–gold(III) complex intermediate, followed by either a domino nucleophilic attack/anti‐endo‐dig cyclization, or the formation of a cyclic oxonium ion with subsequent attack by H₂O. To confirm the proposed mechanistic pathway, we employed MeOH as a nucleophile instead of H₂O to result in a substituted furo[3,2‐c]pyran derivative, as anticipated. The similar furo[3,2‐c]pyran skeleton with a hybrid carbohydrate–furan derivative has also been achieved through pyridinium dichromate (PDC) oxidation of a substituted chiral 3‐formyl furan. The corresponding protected 5‐(1‐alkynyl)‐2,3‐dihydropyran‐4‐one can be synthesized from the monosaccharides (both hexoses and pentose) following oxidation, iodination, and Sonogashira coupling sequences. Furthermore, to demonstrate the potentiality of chiral 3‐formyl furan derivatives, a TiBr₄‐catalyzed reaction of these derivatives has been shown to offer efficient access to 1,5‐dicarbonyl compounds, which on treatment with NH₄OAc in slightly acidic conditions afforded substituted furo[3,2‐c]pyridine.     

2,7,12,17‐Tetraoxa‐3,4:5,6:13,14:15,16‐tetrabenzo­dispiro­[8.1.8.0]­nona­decane

The reaction of bi­phenyl‐2,2′‐diol with 1,1,2,2‐tetrakis­(bromo­methyl)­cyclo­propane leads to two products, namely a propellane‐type compound and a di­spiro‐type compound. The molecular structure of 4,5;6,7‐dibenzo‐3,8,12‐tri­oxa[8.3.1]­propellane has been determined previously by spectroscopic methods. The crystal structure of the di­spiro product, 2,7,12,17‐tetraoxa‐3,4:5,6:13,14:15,16‐tetrabenzodi­spiro[8.1.8.0]­nona­decane, C₃₁H₂₆O₄, revealed that the conformations of the nine‐membered heterocyclic rings are due to interactions between the π‐electron system of the bi­phenyl moiety and the lone electron pairs of the ether O atoms, the repulsion of the lone electron pairs of atoms O1⃛O2 and O3⃛O4, and steric interactions between H atoms in ortho positions. The conformations have C₁ symmetry and can be described approximately as twist‐boat.     

Copper‐Catalyzed Electrophilic Cyclization of N‐Propargylamines with Sodium Sulfinate for the Synthesis of 3‐Sulfonated Quinolines

A convenient and effective protocol for the synthesis of 3‐sulfonated quinolines via copper‐catalyzed electrophilic cyclization of N‐propargylamines has been developed, in which cheap and stable sodium sulfinates were utilized as green sulfonylation reagents. This cascade transformation involves radical addition, cyclization and dehydrogenative aromatization processes in a one‐pot reaction under mild conditions.