The kinetics of the reactions of substituted ethyl arylacetates with quinone methides and structurally related diethyl benzylidenemalonates have been studied in DMSO. The second-order rate constants (lg k₂) correlated linearly with the electrophilicities E according to the linear free-energy relationship lg k₂ = s_N(N + E), allowing us to determine the nucleophilicity parameters N and s_N for these anions. The nucleophilic reactivities of the carbanions vary from N = 27.5 for the parent compound to N = 20.0 for the 4-nitro-substituted derivative.

The kinetics of the reactions of the anions of ethyl arylacetates with quinone methides and diethyl benzylidenemalonates were investigated in DMSO solution. The resulting rate constants follow the linear free-energy relationship lg k₂ = s_N(N + E), which allowed us to derive their reactivity parameters N and s_N.

Several classes of arylphosphorus acid amides have been tested in reactions with alkali metal solutions in liquid ammonia. The outcomes of such reactions depend on the structures of the starting materials. Generally, two processes – Birch reduction or cleavage of the P–aryl bond – can be operative. Diarylphosphinic amides tend to undergo double Birch reduction to afford bis(cyclohexadienyl)phosphinic amides.

Treatment of arylphosphorus acid amides with alkali metal solutions in liquid ammonia results in dearomatisation of the arene fragments and formation of (cyclohexa-1,4-dien-3-yl)phosphorus acid amides. Diarylphosphinic amides tend to undergo Birch reduction of two arene fragments to form bis(cyclohexadienyl)phosphinic amides.

N-Heterocyclic carbene–palladium catalysts are used to promote addition/ring opening of cyclopropenones with terminal alkynes. The ring-opening alkynylation affords alkenyl alkynyl ketones in good yields. For reactions with propargylic esters having an aryl or alkenyl substituent at the propargylic position, [3+2] annulation occurs exclusively to give 4-methylenecyclopentenones.

The ring-opening alkynylation of cyclopropenones with terminal alkynes is catalyzed by palladium–N-heterocyclic carbene (NHC) complexes to provide alkenyl alkynyl ketones. In contrast, [3+2] annulation to give cyclopentenones occurs if secondary propargylic esters bearing an aryl or alkenyl substituent are used.

The synthesis and characterization of a series of BODIPY derivatives substituted with acyclic and cyclic polyamines, in particular, cyclen and homocyclen, are reported. The ¹⁹F NMR, UV/Vis, and fluorescence spectroscopic data of these compounds are discussed. One compound was found to be very selective for Cu^II ions, which makes it a very promising system for Cu^II detection.

The nucleophilic substitution of a 3,5-dichloro-BODIPY derivative with several polyazamacrocycles was investigated. By controlling the BODIPY/macrocycle ratio, some monomeric and dimeric species could be obtained. The photophysical properties of the compounds were studied as was the influence of different cations for one system.

The zwitterionic aza-Claisen rearrangement of optically active N-allylpyrrolidines and α-phenoxyacetyl fluorides proceeds with complete simple diastereoselectivity (internal asymmetric induction) and complete 1,2-asymmetric induction to generate a new C–C bond adjacent to a chiral C-N-Boc functionality. The resulting γ,δ-unsaturated amides were cyclised to give the corresponding pyrrolizidinones, which enabled the determination of the relative configuration of the stereotriads. Vinyl group degradation and a final lactam reduction gave an optically active analogue of (+)-petasinine (a pyrrolizidine alkaloid). Furthermore, the stereotriad-containing amides should be useful key intermediates for the total synthesis of optically active elaeocarpin (an indolizidine alkaloid).

The zwitterionic aza-Claisen rearrangement of optially active N-allylpyrrolidines and α-phenoxyacetyl fluorides proceeds with complete internal and complete 1,2-asymmetric induction to generate a new C–C bond adjacent to a chiral C-N-Boc functionality. The resulting γ,δ-unsaturated amides serve as key chiral intermediates for the total synthesis of pyrrolizidine alkaloid derivatives.

An extensive series of bis-oligobenzamides and bis-oligopyridylamides have been efficiently prepared and studied by X-ray analysis and computational methods. A modular synthesis led to double α-helix mimics bearing between two and ten branched side-chains. The inter-helix angle and distance can be tuned by varying the length and rigidity of the spacer, thereby reproducing the recognition domains of a range of super-secondary structures.

We report the modular synthesis of bis-oligobenzamides and bis-oligopyridylamides as double-helix peptidomimetics with a variety of spacers in which the disposition of strands is tuneable to mimic a range of super-secondary structures.

Oleocanthal, one of the minor components of the phenolic fraction isolated from extra virgin olive oil, is an effective inhibitor of COX enzymes, possessing similar potency to the NSAID ibuprofen. Moreover, it has the capacity to alter the structure of neurotoxic Aβ-amyloid oligomers (ADDLs) and to change the structure of deformed microtubule-associated tau–protein, thus inhibiting the formation of neurofibrillary tangles. It can have, therefore, potential therapeutic use for the treatment of neurodegenerative diseases. In this paper we describe the total synthesis of (±)-oleocanthal in just 8 steps (9 % overall yield) from easily available starting materials. Moreover, resolution of the racemic mixture on an HPLC chiral column provided both enantiomers of oleocanthal in a single operation for biological studies.

Oleocanthal, a component of extra virgin olive oil, possesses anti-inflammatory activity and inhibits the formation of neurofibrillary tangles. In this paper, we have achieved the shortest synthesis of (±)-oleocanthal reported so far from easily available starting materials. Chiral chromatographic resolution of the mixture provided both enantiomers for biological studies.

The formation of amides through the in situ activation of carboxylic acids with [Et₂NSF₂]BF₄ is presented. A wide range of carboxylic acids and amines were used to produce the corresponding amides in up to 99 % yield. The reaction of hindered amines was also possible in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) under slightly modified conditions. An enantiopure carboxylic acid and amine were both shown to react without racemization.

The formation of amides through the in situ activation of carboxylic acids with [Et₂NSF₂]BF₄ is presented. A wide range of carboxylic acids and amines were used to produce the corresponding amides in up to 99 % yield. The reaction with hindered amines was also possible under slightly modified conditions. An enantiopure carboxylic acid and amine were shown to react without racemization.

Myrtucommulone A (1), which was isolated from myrtle and other species of the myrtaceae family, was synthesized through an enantioselective Michael addition of isobutyryl phloroglucinole (5) to isobutylidene syncarpic acid (4) that was induced by a chiral Al–Li–BINOL (1,1′-bi-2-naphthol) complex [(S,S)-ALB]. Because there is significant steric crowding in Michael acceptor 4, myrtucommulone A (1) was obtained with an ee value of 70 % along with meso-1 in 77 % chemical yield.

Myrtucommulone A (1) is a phloroglucinol derivative that is isolated from myrtle (Myrtus communis) and shows antibiotic, anti-inflammatory, and apoptosis-inducing activities. For pharmacological and racemization studies, we synthesized (+)-1 enantioselectively with an ee value of 70 % in two steps from isobutyryl phloroglucinole, isobutylidene syncarpic acid (4), using first (S,S)-8 and then (R,R)-8.

The preparation of symmetrical unsaturated diesters of dioe first was the reaction of mixed anhydrides, obtained from α,β-unsaturated acids and benzoyl chloride, with diols 3 (primary), 5 (secondary), and 7 (primary), i.e., Yamaguchi–SantaLucía's method, however only the symmetrical diacrylates of diols 5 and 7 were obtained quantitatively. In the other ten cases studied the reactions led to mixtures of symmetrical and unsymmetrical diesters that were difficult to separate. The mixed anhydrides did not react with the tertiary diols 4 (TADDOL) and 8. The average yield obtained in desired symmetrical diesters in the 12 cases studied was 54 %. The acylation of the diols with the anhydrides of the unsaturated acids, was found to be an excellent method, leading to the symmetrical unsaturated diesters of diols 3, 5, 7 as the only products of reaction, in an average yield of 83 %. Unfortunately, the method could not be applied to diesters derived from the tertiary diols 4 (TADDOL) and 8. The third method studied was the reaction between the alkoxides prepared with solutions of nBuLi in ether with the unsaturated acid chlorides at –50 °C, i.e., the Kaiser–Woodruff protocol. This was found to be the best of the three methods tested. The method was applied with success to the synthesis of the desired unsaturated diesters derived from diols 3–5, 7, and 8. The average yield of the 19 cases studied was 78 %.

The synthesis of symmetrical unsaturated diesters of types A–C, obtained from primary, secondary, and tertiary diols derived of dimethyl (+)-tartrate and galactaric acid, is reported. Of the four methods tested, the best was the reaction between the diols and unsaturated acid chlorides in the presence of nBuLi in diethyl ether at –50 °C; this approach affords the diesters in an average yield of 78 %.

A diastereoselective synthesis of isoindole-fused diazacyclooctaindenone derivatives has been accomplished through tandem ring-opening and ring-closing of spirochromene derivatives triggered by different aliphatic 1,2-diamines. When ethanolic solutions of spirochromenes are refluxed with different aliphatic 1,2-diamines such as 1,2-ethylenediamine, (±)-1,2-propylenediamine and (±)-trans-1,2-cyclohexanediamine, the isoindole-fused eight-membered heterocycles are formed in moderate to high yields within 5–15 min.

A diastereoselective synthesis of isoindole-fused diazacyclooctaindenone derivatives has been accomplished through tandem ring-opening and ring-closing of spirochromene derivatives triggered by different aliphatic 1,2-diamines.

A convenient and efficient two-step route to 6H-Isoindolo[2,1-a]indol-6-ones has been developed starting from o-nitrobenzaldehydes. The methodology involves Wittig reaction followed by tandem reductive cyclization–lactamization. A series of isoindoloindolones incorporating different substituents on the indole nucleus has been prepared.

A two-step route involving Wittig reaction followed by tandem reductive cyclization–lactamization is presented for the synthesis of 6H-Isoindolo[2,1-a]indol-6-ones.

The unique synthesis of 3-amino-4-nitrothiophenes 2 provides easy access to reference species of a new family of push-pull substituted thiophenes. The chemoselective modification of 2 into suitable derivatives was accomplished by selective S-oxidation of the vinylsulfanyl unit, followed by substitution of the vinylsulfinyl group of 3 by nucleophiles. Dihalothiophenes were formed this way in very good yields. A subsequent selective dehalogenation at the 2, 5 or 2 and 5 positions also proved feasible, and the push-pull unit was untouched. The new 2,5-dihalothiophenes could be interesting monomers for conducting polymers.

Starting from per-substituted 3-amino-4-nitrothiophenes with a 2-chloro- and a 5-vinylsulfanyl substituent the formation of vinyl-S-oxides and subsequent substitution against nucleophiles is reported. Additionally, dehalogenation of the formed halothiophenes is possible with three different methods, which lead to selective dehalogenation at the 2, 5 or 2 and 5 position.

Three different 2,2′-binaphthylphosphites were synthesized, starting from suitable derivatives of cholic or deoxycholic acids and 1,1′-dihydroxy-2,2′-binaphthyl, and their stereochemical features were analyzed by CD and NMR spectroscopy. The spectroscopic data clearly demonstrate the capability of the cholestanic backbone to induce a M prevalent screw sense to the flexible binaphthyl moiety, giving rise to tropos ligands. The extent of the prevalence of the M sense of twist depends on the position at which the binaphthylphosphite moiety is linked on the bile acid skeleton. The three phosphites were mixed with [Rh(COD)₂][BF₄] and the resulting complexes were analyzed by variable temperature ³¹P NMR spectroscopy, thereby obtaining information on their stereochemical characteristics, which reflect the different asymmetric induction capability of the ligands.

Chirality transfer from the cholestanic backbone of bile acid derivatives to the flexible 2,2′-binaphthyl-1,1′-diylphosphite moiety was obtained in the synthesis of three different phosphite ligands.

Despite their simple structures, synthesis of 1(or 3)-acyl-sn-glycerols remains a challenge that cannot be ignored because of facile acyl migrations, which not only complicate the synthesis but also make direct GC or HPLC analysis unfeasible. Assessment of the optical purity of monoacylglycerols has, to date, relied almost exclusively on specific rotation data, which are small in value and thus insensitive to impurities. Now, a simple means to “magnify” the small specific rotations has been found, along with practical methods for the measurement of both 1,2- and 1,3-acyl migrations, which offer a convenient and straightforward alternative to Mori's NMR analysis of Mosher esters. With the aid of these methods, a range of conditions for deacetonide removal were examined en route to the synthesis of two natural monoacylglycerols. Refined hydrolysis conditions, along with useful knowledge about the solubility and reactivity of substrates with an ultra long alkyl chain are also presented.

Because of facile acyl migrations, the synthesis of enantiopure 1(or 3)-acyl-sn-glycerols is much more difficult than their seemingly very simple structures may imply. Even assessment of their optical purity is a difficult task because of the lack of a feasible means of analysis. Now, new findings have changed everything.

The reaction of metal alkoxides with β-substituted 2-(p-tolylsulfonyl)acetylenes, involving an anti-Michael addition reaction followed by the in situ elimination of the sulfonyl moiety, provides a direct method for the synthesis of alkyl alkynyl ethers bearing aryl or TIPS groups joined to the triple bond. Arylalkynyl ethers derived from primary alkoxides are in situ hydrolyzed into arylacetic esters.

Ynol ethers can be directly obtained under mild conditions by reaction of KOR with β-substituted 2(-p-tolylsulfonyl)acetylenes. Only arylacetylenes (with KOtBu) and TIPS-acetylenes provide good yields of alkyl ethynyl ethers

Propargylallenes offer the varied reactivity patterns of two different multiple bond linkages either separately or in concert. Their syntheses, structures, rearrangement mechanisms and synthetic utility are reviewed, together with their behaviour when treated with transition-metal reagents such as gold(I), silver(I), platinum metals or metal carbonyls.

Propargylallenes offer varied reactivity patterns arising from the presence of two different multiple bond linkages, either separately or in concert. We review their syntheses, structures, rearrangement mechanisms and synthetic utility, together with their behaviour on treatment with transition-metal reagents such as gold(I), silver(I), platinum metals or metal carbonyls.

We report a practical and modular approach to obtain two different types of 17-membered ring macrocyclic compounds through an intramolecular Heck reaction. These macrocyclic compounds are functionalized, that is, they contain two contiguous stereogenic hydroxy functional groups and an amino acid moiety in the macrocyclic ring skeleton. The macrocycles were then screened against a zebrafish assay to determine the antiangiogenesis activity of these small molecules. Macrocyclic compound 2.2a was identified as a potent inhibitor at 2.5 μM, whereas its acyclic precursor and the other related macrocyclic compounds did not show any effect.

A practical and modular approach to obtain 17-membered macrocyclic compounds through an intramolecular Heck reaction is reported. These macrocycles contain two contiguous stereogenic hydroxy functional groups and an amino acid moiety in the macrocyclic ring skeleton. The macrocycles were then screened against a zebrafish assay to determine the antiangiogenesis activity of these small molecules.

A modular approach to explore the macrocyclic chemical space around an aminoindoline scaffold is developed. This is achieved by incorporating an amino acid moiety and subsequent “stitching technology”. Through screening of a zebrafish assay, several antiangiogenesis agents are identified.

A modular approach to explore the macrocyclic chemical space around an aminoindoline scaffold is developed. This is achieved by incorporating an amino acid moiety and subsequent “stitching technology”. Through screening of a zebrafish assay, several antiangiogenesis agents are identified.

A general method for the vicinal dioxygenation of enecarbamates was developed by using PhI(OAc)₂ as the sole oxidant under extremely mild conditions, thus avoiding starting material decomposition. This methodology, which is an alternative to common dioxygenation processes catalyzed by transition metals, provides easy access to functionalized β-acetoxy-α-amido ethers and α-amido-β-oxytetrahydrofurans in moderate to good yields.

A general method for the vicinal dioxygenation of enecarbamtes is developed by using PhI(OAc)₂ as the oxidant. The reaction is carried out without the assistance of a transition metal under mild conditions to afford β-oxy-α-amido ethers in good yields. Nu = nucleophile, LA = Lewis acid.

A novel series of 1,4-disubstituted 1,2,3-triazole-containing potassium trifluoroborates were prepared in good to excellent yields from the corresponding organohalides and potassium ethynyltrifluoroborate through a regioselective one-pot Cu-catalyzed azide–alkyne cycloaddition (CuAAC) reaction. Further Suzuki–Miyaura cross-coupling of these (organo-1,2,3-triazol-4-yl)trifluoroborates with aryl and alkenyl bromides by using a PdCl₂(dppf)·CH₂Cl₂/TBAB [dppf = 1,1′-bis(diphenylphosphanyl)ferrocene, TBAB = tetrabutylammonium bromide] system under microwave irradiation was explored.

The preparation of potassium (1-organo-1H-1,2,3-triazol-4-yl)trifluoroborates from potassium ethynyltrifluoroborate and alkyl or aryl halides by employing a regioselective one-pot Cu-catalyzed azide–alkyne cycloaddition (CuAAC) is elaborated. This strategy allows unrestricted access to an infinite variety of 1,4-disubstituted 1,2,3-triazoles.

A practical and efficient two-step protocol for the synthesis of several new 4,6,7,8,8a,9-hexahydropyrrolo[1,2-a][1,2,3]triazolo[1,5-d]pyrazines is described. The first step involves the AuBr₃-catalyzed three-component coupling reaction of terminal alkynes, aldehydes, and amines under solvent-free conditions to provide the requisite propargylamines. The reaction tolerates a high structural diversity, requires only short reaction times, gives high diastereoselectivities, and is environmentally benign. Furthermore, the propargylamine products undergo catalyst-free intramolecular azide–alkyne [3 + 2] dipolar cycloaddition reactions to give the 4,6,7,8,8a,9-hexahydropyrrolo[1,2-a][1,2,3]triazolo[1,5-d]pyrazines in excellent yields and with excellent diastereoselectivities.

A two-step protocol for the synthesis of 4,6,7,8,8a,9-hexahydropyrrolo[1,2-a][1,2,3]triazolo[1,5-d]pyrazines was developed. The first step is an AuBr₃-catalyzed three-component coupling of aldehydes, alkynes, and an amine to give propargylamines under solvent-free conditions at 80 °C. The second step is the ring-closure to give the final products under mild reaction conditions.

An efficient and highly regioselective one-pot three-component synthesis of previously inaccessible and synthetically demanding 3-(cycloalkyl/alkyl/arylamino)-5-aryl/alkylisoxazoles has been achieved by the cyclocondensation of β-oxo dithioesters, amines and hydroxylamine in ethanol at reflux. This transformation proceeds via an in situ generated β-oxothioamide by the reaction of the β-oxo dithioester and amine, which undergoes nucleophilic attack by hydroxylamine followed by intramolecular cyclization with the oxo functionality and subsequent dehydration to give 5-substituted 3-aminoisoxazoles as a single regioisomer in good yields. Furthermore, the mechanism of the reaction has been established experimentally and shown to be in agreement with the hard and soft (Lewis) acid and base (HSAB) theory.

A highly regioselective synthesis of 5-substituted 3-aminoisoxazoles has been achieved by a one-pot three-component coupling of β-oxo dithioesters, amines and hydroxylamine in ethanol at reflux via an in situ generated β-oxo thioamide intermediate. The mechanism of the reaction has been established experimentally and shown to be in agreement with the HSAB theory.

(α-Benzyloxycarbonyl-aminoacyl)benzotriazolides (Cbz = benzyloxycarbonyl) underwent a coupling reaction with α-hydrazino acids under microwave irradiation to form hybrid hydrazino dipeptides (42–71 %). Chiral acylations of β-N-Cbz-α-hydrazino acylbenzotriazolides were successfully carried out with N-, S-, O-, and C-nucleophiles in yields of 49–88 %.

Benzyloxycarbonyl-protected hybrid hydrazino dipeptides and benzyloxycarbonyl-protected hydrazino aminoacyl conjugates with N-, S-, O-, and C-nucleophiles were prepared by using benzotriazole methodology.

A catalytic enantioconvergent process has been developed for the conversion of racemic allyl indolenin-3-carboxylates into enantiomerically enriched C3-quaternary indolenines. A Pd-catalyzed decarboxylative allylic alkylation reaction was employed for both stereoablation of the racemic allyl indolenin-3-carboxylates and enantioselective formation of the quaternary carbon center.

The enantioconvergent conversion of racemic allyl indolenin-3-carboxylates into enantiomerically enriched C3-quaternary indolenines is reported. A Pd-catalyzed decarboxylative allylic alkylation reaction is employed for both stereoablation and enantioselective formation of the quaternary carbon center.

Upon treatment with sodium azide in DMF, bisalkynes undergo chemoselective [3+2] cycloaddition followed by oxidative cleavage of the other alkyne unit by atmospheric oxygen. The neighboring triazoloyl ion is found to assist the cleavage process ultimately to deliver an acid and an aldehyde.

Cycloaddition of azide with a bisalkyne chemoselectively forms a triazole, which subsequently undergoes oxidative cleavage by atmospheric oxygen to yield a carboxylic acid and an aldehyde. The mechanism for this reaction is investigated in depth.

This microreview discusses recent efforts in chemical synthesis to design divergent pathways either to access diverse natural products from a common intermediate or to produce diverse libraries of compounds reminiscent of natural products. These efforts are generally based on the development and use of powerful complexity-generating reactions and cascade reactions. A panel of eighteen examples is used to illustrate different strategies.

Strategically divergent: Designing synthetic pathways from pluripotent intermediates. Getting more molecules for your carbon.

A scalable approach to the syntheses of enantiomerically pure cis-1,2-cyclohexanediamines as well as exo- and endo-7-azabicyclo[2.2.1]heptan-2-amines is reported that utilizes meso-tert-butyl 2,3-bis(phenylsulfonyl)-7-azabicyclo[2.2.1]hept-2-ene-7-carboxylate as a starting material.

The 7-azabicyclo[2.2.1]heptane skeleton was exploited to achieve a new approach to the syntheses of enantiomerically pure cis-1,2-cyclohexanediamine derivatives and conformationally rigid 7-azabicyclo[2.2.1]heptan-2-amines. This was achieved on a multigram scale without producing the undesired diastereomers.

We report herein a synthetic pathway to new 6(5)-bromo-5(6)-methylimidazo[1,2-a]imidazolin-2-ones. The synthetic potential of these scaffolds was demonstrated by displacing bromine by Suzuki–Miyaura cross-coupling reactions. A large panel of boronic acids (aryl, heteroaryl or vinyl) could easily be introduced, giving access to a large and diversified library of 6(5)-substituted 5(6)-methylimidazo[1,2-a]imidazolin-2-ones.

A new route to 6(5)-bromo-5(6)-methylimidazo[1,2-a]imidazolin-2-ones have been developed. A novel and effective strategy of functionnalization of these scaffolds throught Suzuki–Miyaura cross coupling reactions is reported. Thanks to this methodology, a large panel of boronic acids were easily introduced, giving access to a diversified library of 6(5)-substituted 5(6)-methylimidazo[1,2-a]imidazolin-2-ones.

Carbohydrate–carbohydrate interactions (CCI) are mediated by complexation of metal ions. Angyal postulated on the requirements for hydroxy group arrangement in pyranoses to account for metal-ion complexation. These requirements are particularly well fulfilled in α-ido- and α-talopyranosides, whose ring hydroxy groups have all axial and axial-equatorial-axial configurations, respectively. Surface plasmon resonance (SPR) and gold-nanoparticle techniques have proved to be powerful tools to investigate CCIs. Benzaldehyde-functionalized glycans can be used for attachment to both gold nanoparticles and SPR sensor surfaces. Therefore, benzaldehyde-equipped ido- and talopyranosides were synthesized by the almost forgotten Paulsen acetoxonium rearrangement. This approach provides peracetylated idose and talose in only two steps from common glucose and galactose precursors, respectively, in overall yields of up to 41 % and, therefore, avoids long and laborious procedures to obtain these rare carbohydrates. The derivatives are being used in ongoing CCI studies using SPR to test Angyal's postulate about the structural requirements for hydroxy group arrangements.

Almost forgotten: The Paulsen acetoxonium rearrangement provides a facile and rapid access to rare carbohydrates. Through a cascade of antimony pentachloride induced acetoxonium rearrangements, ido- and talopyranose derivatives can be synthesized from simple glucose and galactose precursors in a one-pot procedure.

The copper-catalysed (10 mol-% CuBr·SMe₂, CuCN·LiCl or CuI/PPh₃) addition of RMgBr to the pentafulvene 1-(cyclopenta-2,4-dien-1-ylidenemethyl)-2-methoxybenzene allows the formation of cyclopentadienyl derivatives with α-CHR(2-MeOPh) sidechains (R = Me, Et, nBu, iBu, allyl, Ph) without H^– transfer. The deprotonation of these sec-alkyl-substituted cyclopentadienyls followed by the addition of TiCl₄ allows the isolation of TiCl₂{η⁵-C₅H₄CHR(2-OMePh)} as rac/meso mixtures that show activity against human colon, breast and pancreatic cell lines (GI₅₀ 2.3–42.4 μM).

The direct addition of alkyllithium and Grignard reagents with β-hydrogen atoms to fulvenes has been dogged with the problem of competing hydride transfer. Copper catalysis overcomes this and allows access to titanocene dichlorides with high anticancer activity.

Preorganised dipeptide mimics containing a 3,4-disubstituted oxazolidin-2-one, a flexible methylene group, and a 1,4-disubstituted triazole have been prepared in a few steps and high yield by copper-catalysed azide–alkyne cycloaddition (CuAAC). The combination of these three moieties allows the formation of a new dipeptide mimic that favours the formation of bent conformations, as we could demonstrate by IR and ROESY analysis.

Rigid, flexible, rigid: the combination of a 3,4-disubstituted oxazolidin-2-one ring, a flexible methylene group and a 1,4-disubstituted triazole ring allows the formation of a new dipeptide mimic that favours the formation of bent conformations.

This paper describes a new class of macrocyclic peptides that fold to form β-sheet structures. These macrocyclic β-sheets consist of a peptide sequence strand linked through two δ-linked ornithine turn units to a peptide template strand containing a single N-methyl amino acid. The macrocycles were readily prepared from commercially available amino acids by solid-phase peptide synthesis followed by solution-phase cyclization. ¹H NMR spectroscopic studies showed that macrocycles containing amyloidgenic pentapeptide sequences from amyloid β-peptide, tau protein, the B-chain of insulin, and human prion protein fold to form β-sheet structures.

Recipe for β-Sheets: Combine one N-methyl-amino acid, two δ-linked ornithine turn units, and nine α-amino acids by solid-phase peptide synthesis. Cyclize in solution, deprotect, and purify by RP-HPLC. Confirm folding by ¹H NMR ROESY and magnetic anisotropy studies. Serve to laboratories interested in studying and inhibiting amyloid aggregation or studying β-sheet assembly.

A metal-free and completely regioselective three-component synthesis of highly functionalized pyridines from 1,3-dicarbonyl derivatives and Michael acceptors has been achieved. Activated Michael acceptors, that is, β,γ-unsaturated α-oxo carbonyl derivatives, were utilized, allowing substitution at the 4-position and remarkable functional diversity at the 2-position of the pyridine ring. The scope and limitations of this environmentally friendly domino reaction are disclosed, with full experimental data, and the results of mechanistic investigations are discussed.

The three-component synthesis of polysubstituted pyridines starting from 1,3-dicarbonyl compounds, α,β-unsaturated carbonyl derivatives and ammonium acetate has been studied, including the scope and mechanism. This methodology is a rare example of a totally regioselective multicomponent access to highly substituted pyridines that complies with many of the stringent criteria of sustainable chemistry.

N-Tosyl 3,3-dialkyl-2-(tert-butyldiphenylsilylmethyl)azetidines rearrange smoothly into the corresponding 2-alkenyl-3-(tert-butyldiphenylsilyl)amines upon exposure to BF₃·OEt₂ in CH₂Cl₂. The reaction involves sequential σ_C–N bond cleavage, 1,2-migration of the N-tosyl-aminomethyl group, and deprotonation of the resultant tert-carbenium ions. For the instance in which the carbenium ion formed from migration of the N-tosyl-aminomethyl group is highly stable by virtue of being, for example, tertiary as well as benzylic, the migration takes place in sync with σ_C–N bond cleavage, which leads to high configurational control at the tert-butyldiphenylsilylmethyl-bearing carbon atom in the product.

In contrast to N-tosyl-substituted 3-alkyl-2-(tert-butyldiphenylsilylmethyl)azetidine, the corresponding 3,3-dialkyl derivative rearranges into N-tosyl-2-alkenyl-3-(tert-butyldiphenylsilyl)amine upon exposure to BF₃·OEt₂. The reaction involves sequential σ_C–N bond cleavage, 1,2-migration of the N-tosyl-aminomethyl group, and deprotonation of the resultant tert-carbenium ion.

A novel technique to label ortho-, meta-, and para-trimethylsilyl-substituted aryl substituents with radioactive iodide is described. The method takes advantage of the ipso-directing and activating properties of trimethylsilyl substituents on the arenes. The method was demonstrated on a griseofulvin analogue with promising anticancer properties and on lidocaine, a widely used local anesthetic drug. Treatment of a trimethylsilyl precursor with Tl(OCOCF₃)₃ followed by Na¹²⁵I consistently afforded radioactive purities over 95 % in all cases.

A mild and selective method for radioiodination of aromatic compounds is described. This method is used to label three regioisomers of an analogue of griseofulvin with potent anticancer activity. The method takes advantage of the ipso-directing effect of a trimethylsilyl (TMS) substituent and is also demonstrated to work for the local anesthetic lidocaine.

The solution conformations of the αγ-hybrid oligopeptides Boc–[Aib–γ⁴(R)Val]_n–OMe (n = 1–8) in organic solvents have been probed by NMR, IR, and CD spectroscopic methods. In the solid state, this peptide series favors C₁₂-helical conformations, which are backbone-expanded analogues of 3₁₀ helices in α-peptide sequences. NMR studies of the six- (n = 3) and 16-residue (n = 8) peptides reveal that only two NH protons attached the N-terminus residues Aib(1) and γ⁴(R)Val(2) are solvent-exposed. Sequential N_iH–N_i+1H NOEs characteristic of local helical conformations are also observed at the α residues. IR studies establish that chain extension leads to a large enhancement in the intensities of the hydrogen-bonded NH stretching bands (3343–3280 cm^–1), which suggest elongation of intramolecularly hydrogen-bonded structures. The development of C₁₂-helical structures upon lengthening of the αγ sequence is supported by the NMR and IR observations. The CD spectra of the (αγ)_n peptides reveal a negative maximum at ca. 206 nm and a positive maximum at ca. 192 nm, spectral feature that are distinct from those of 3₁₀ helices in α-peptides.

The formation of C₁₂-helical structures in the hybrid αγ oligopeptides Boc–[Aib–γ⁴(R)Val]_n–OMe in solution is demonstrated by NMR and IR methods. The intramolecularly hydrogen-bonded solution conformations resemble those previously determined by X-ray crystallography. C₁₂-helix development has also been monitored by far-UV CD.

The synthesis of 3-azabicyclo[3.2.0]heptane-6-carboxylic acid and 7-substituted derivatives was developed as bicyclic analogues of γ-aminobutyric acid. A sensitized, intermolecular [2+2] photocycloaddition of maleic anhydride with N-protected 3-pyrroline served as the key step in these syntheses. Upon transformation of the anhydride function of the primary cycloaddition product, 6-monosubstituted and 6,7-disubstituted 3-azabicyclo[3.2.0]heptane derivatives were obtained.

A sensitized, intermolecular [2+2] photocycloaddition of maleic anhydride and N-protected 3-pyrroline is the key step in the synthesis of azabicyclo[3.2.0]heptane derivatives. Thus, new γ-aminobutyric acid analogues with a carboxy function in the 6-position, either with or without an additional functional group in the 7-position of the azabicyclo[3.2.0]heptane skeleton, were synthesized.

The application of the o-nitrobenzyl (oNBn) group is demonstrated. This practical methodology allows the stereocontrolled synthesis of glucosides with a 1,2-trans linkage. This new ether-type arming group can broadly extend the concept of the use of participating groups in glycosylation reactions. Easy protection and deprotection of the oNBn group further confirms its usefulness in synthesis.

The application of o-nitrobenzyl (oNBn) ether as an arming participating group is demonstrated. This practical methodology allows the stereocontrolled synthesis of glucosides with a 1,2-trans linkage.

An efficient catalytic protocol for the synthesis of δ,δ-bis(aryl)-substituted β-keto esters has been developed. This method involves the Lewis acid catalysed disubstitution reaction of ester-substituted silyl enol ether acetals with a series of aromatic nucleophiles to afford valuable functionalized β-keto esters with several sites available for further derivatisation.

An efficient protocol for the conversion of silyl enol acetals into δ,δ-bis(aryl) β-keto esters was developed. In the presence of an aromatic nucleophile, activation of the acetal by a catalytic amount of Lewis acid facilitates the disubstitution reaction to afford a series of valuable functionalised β-keto esters.

A series of meso-CF₃-4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) dyes with aryl and hetaryl substituents at the C-3 and C-5 positions, both symmetric and asymmetric, have been synthesized in 36–90 % yields by a new strategy involving as the key step the condensation of 2,2,2-trifluoro-1-(5-arylpyrrol-2-yl)-1-ethanols with diverse 2-arylpyrroles. The starting 2,2,2-trifluoro-1-(5-arylpyrrol-2-yl)-1-ethanols are easily prepared by reduction of the available 2-trifluoroacetyl-5-arylpyrroles. The synthesized dyes fluoresce in a longer wavelength region (626–698 nm) with high quantum yield (0.84–0.99).

A new strategy for the synthesis of highly efficient symmetric and asymmetric BODIPY fluorophores that combine trifluoromethyl and 3,5-aryl substituents has been developed. The key step is the P₂O₅-promoted condensation of 2,2,2-trifluoro-1-(5-arylpyrrol-2-yl)-1-ethanols with diverse 2-arylpyrroles.

Substituted phenanthridines, such as the natural product trispheridine, have been accessed by the practical photochemical cyclization of N-benzylanilines. Functionalities, with a focus on fluoro substituents and protected catechols, are well tolerated on both the A and C rings. The phenanthridines were accessed in good to very good yields (up to 95 %) from iodinated substrates, whereas brominated substrates performed poorly in comparison (0–48 %).

Substituted phenanthridines, such as the natural product trispheridine, can be accessed by the practical photochemical cyclization of N-benzylanilines, with functionalities tolerated on both the A and C rings. The phenanthridines are accessible in good to very good yields (up to 95 %) from iodinated substrates, whereas brominated substrates perform poorly in comparison (0–48 %).

This paper describes the design, synthesis and structural analysis of a 3-O-alkylated aromatic oligoamide that incorporates an additional hydrophilic 6-O-alkyl substituent in the central monomer. This oligomer exhibits low μM inhibitory potency against the p53–hDM2 interaction compared with its unfunctionalised counterpart and significantly improved solubility.

A 3-O-alkylated aromatic oligoamide foldamer incorporating an additional and hydrophilic 6-O-alkyl substituent in the central monomer is shown to have improved solubility, adopt an active binding conformation and disrupt the p53–hDM2 interaction.

Extensive analysis by NMR spectroscopy of the delipidated lipopolysaccharide of Shigella flexneri serotype 6 strain MDC 2924-71 confirmed the most recently reported structure of the O-antigen repeating unit as {→4)-β-D-GalpA-(1→3)-β-D-GalpNAc-(1→2)-α-L-Rhap_3Ac/4Ac-(1→2)-α-L-Rhap-(1→}, and revealed the non-stoichiometric acetylation at O-3_C/4_C. Input from the CASPER program helped to ascertain the fine distribution of the three possible patterns of O-acetylation. The non-O-acetylated repeating unit (ABCD) corresponded to about 2/3 of the population, while 1/4 was acetylated at O-3_C (_3AcCDAB), and 1/10 at O-4_C (_4AcCDAB). Di- to tetrasaccharides with a GalpA residue (A) at their reducing end were synthesized as their propyl glycosides following a multistep linear strategy relying on late-stage acetylation at O-3_C. Thus, the 3_C-O-acetylated and non-O-acetylated targets were synthesized from common protected intermediates. Rhamnosylation was most efficiently achieved by using imidate donors, including at O-4 of a benzyl galacturonate acceptor. In contrast, a thiophenyl 2-deoxy-2-trichloroacetamido-D-galactopyranoside precursor was preferred for chain elongation involving residue B. Final Pd/C-mediated deprotection ensured O-acetyl stability. All of the target molecules represent parts of the O-antigen of S. flexneri 6, a prevalent serotype. Non-O-acetylated oligosaccharides are also fragments of the Escherichia coli O147 O-antigen.

The repeating unit of the O-specific polysaccharide (PS) from Shigella flexneri serotype 6 (SF6) strain MDC 2924-71 has been studied by NMR spectroscopy, confirming a non-stoichiometric O-acetylation at one of the rhamnosyl residues. The synthesis of di- to tetrasaccharide derivatives with and without mono-O-acetylation is reported. Structures are common to SF6, SF6a, and Escherichia coli O147.

The cascade annulation-lactonization of phthalides with α-carboxyfurylacrylates in the presence of lithium hexamethyldisilazide (LiHMDS) provides both convergent and semiconvergent regioselective syntheses of neo-tanshinlactones in moderate yields. This methodology also offers an avenue for the direct syntheses of hitherto unreported 6-alkoxycarbonyl-substituted neo-tanshinlactones and their heterocyclic analogues. A new synthesis of 4-alkyl phthalides was developed on the basis of a combination of a Duff reaction and Fürstner cross-coupling.

The cascade benzannulation-lactonization of phthalides with α-carboxyfurylacrylates was employed as the key reaction for the concise synthesis of neo-tanshinlactone.

A novel dehydrogenation reaction of perfluoroalkyl ketones by the oxoammonium salt 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (4-NHAc-TEMPO⁺BF₄^–, Bobbitt's salt, 1) is described. The reaction proceeds under mildly basic conditions and appears to be unique to perfluoroalkyl ketones. A proposed mechanism for this unusual transformation is given. The byproduct of the reaction, 4-acetylamino-2,2,6,6-tetramethyl-1-piperidinyloxy (1a), can easily be recovered and used to regenerate the oxoammonium salt.

The dehydrogenation of perfluoroalkyl ketones by using an oxoammonium salt is reported. The reaction proceeds under mildly basic conditions and affords α,β-unsaturated products in fair to excellent yields. The reaction likely proceeds through a two-step sequence. The spent oxidant can easily be recovered and used to regenerate the oxoammonium salt.

Selenoisotryptophan and its higher homologues were synthesized by Sonogashira coupling of iodophenyl methyl selenide and alkynyloxazolidines followed by iodocyclization as the key step. Sonogashira coupling of 3-iodobenzoselenophene with ethynyloxazolidine allowed the synthesis of selenohomotryptophan.

Selenium analogues of isotryptophan and homoisotryptophan derivatives were synthesized by Sonogashira coupling of iodophenyl methyl selenide with alkynyloxazolidines followed by iodocyclization as the key step. Sonogashira coupling of 3-iodobenzoselenophene with ethynyloxazolidine afforded the selenohomotryptophan derivative.

Even though aromatic oligoamides composed of aromatic amino acids in a “one-way sequence” attract ever increasing research interest, backbones connected through ortho-linked aromatics remain rare. Herein, we present the first synthesis and study of N-alkylated ortho-aminomethyl-benzamides termed “ortho-arylopeptoids”. The ortho-arylopeptoids may, with a few exceptions, be synthesized either in solution or on solid-phase using unique and highly efficient submonomer methods with similar levels of high generality and efficiency to those previously demonstrated for meta- and para-arylopeptoids. NMR studies indicated a more restricted rotation about the amide bonds in ortho-arylopeptoids, presumably due to a more congested backbone structure resulting from the ortho-connectivity pattern. Intriguingly, tert-butyl and phenyl side chains offer complete control over the amide conformations; whereas arylopeptoid residues with tert-butyl side chains adopt a 100 % cis amide conformation, the opposite 100 % trans amide conformation was observed in arylopeptoids with phenyl side chains. The tert-butyl moiety can furthermore serve as a protecting group during synthesis, which can later be removed to allow the amide to adopt a 100 % trans conformation instead.

We present the first synthesis and study of N-alkylated ortho-aminomethyl-benzamides termed “ortho-arylopeptoids”. These compounds can be synthesized both on solid-phase and in solution using a unique submonomer method and constitute a rare example of aromatic oligoamides with ortho-connectivity. The tert-butyl and phenyl side chains offer complete control over the amide conformations.

A protocol for direct access to C-4-functionalized Neu5Ac2en derivatives by allylic substitution of an α-acetoxy group with various nucleophiles is reported. The DANA acetamido group is exchanged for a trifluoroacetylamido group (as in FANA) to avoid the formation of a stable 4,5-oxazoline. With thiols, the reaction involves an initial attack at the anomeric carbon (Ferrier reaction) under kinetic control, followed by an equilibration of the nucleophile to the thermodynamically more stable 4-position.

A general access to C-4-substituted Neu5Ac glycals combining elements of molecules showing anti-neuraminidase activity.

A simple chemoenzymatic asymmetric route has been developed for the production of antimigraine agent (R)-Frovatriptan. Lipases and oxidoreductases have been identified as ideal biocatalysts for the production of enantiopure adequate synthetic intermediates under safe and environmentally friendly conditions. (S)-3-Hydroxy-2,3,4,9-tetrahydro-1H-carbazole-6-carbonitrile, an optimal building block for the synthesis of the drug, has been efficiently prepared through Candida antarctica lipase type B catalyzed acylation of its corresponding racemic mixture or alcohol dehydrogenase A mediated bioreduction of the corresponding ketone. The inversion of the chiral center has been identified as a key step, optimizing the process to avoid partial racemization. Finally, amine functionalization and nitrile hydrolysis have allowed the production of (R)-Frovatriptan in enantiomerically pure form.

A simple chemoenzymatic preparation has been developed for the production of serotonin receptor agonist (R)-Frovatriptan starting from inexpensive starting materials. The enzymatic action towards ketone or alcohol intermediates is the key step for the asymmetric total synthesis of this drug.

New fused cis- and trans-furano-pyran β-amino acids were synthesized. The cis-monomer was utilized for the synthesis of α/β-peptides (tetra-, penta-, hexa- and hepta-mers), to understand its impact on helix formation. Conformational analysis of the peptides with a “β-α-β” sequence at the C-terminus showed the presence of a left-handed 9/11-helix in which the nine-membered H-bond motif is found to be weak and contributes only a small amount of electrostatic interaction to helix stabilization. Peptides with an “α-β-α” sequence at the C-terminus revealed the presence of a left-handed 9/11-helix involving the central residues and display a clear 12-membered turn at the C-terminus. In both the cases, the 9/11-helix was stabilized by a seven-membered H-bond at the N-terminus.

α/β-Peptides were synthesized from alternating fused furano-pyran β-amino acid/L-Ala units, and their conformations were analyzed. The system adopted a left-handed 9/11-helix that was supported by 7-mr H-bonding at the N-terminus.

Aryl nitriles were efficiently synthesized through copper-mediated cyanation of aryl halides using benzyl cyanide as the cyanide source. Aryl halides with various substituents on the aromatic ring afforded the corresponding aryl nitriles in 32–97 % yields (25 examples). This reaction could also be carried on a gram scale by using commercially available reagents. Additionally, a C–H bond oxidation and a C–CN cleavage are proposed to be involved in this cascade process.

An efficient, copper-mediated cascade synthesis of aryl nitriles from aryl halides using benzyl cyanide as the cyanide source is described. Compared with traditional copper-mediated cyanation reactions, this approach effectively avoided the use of toxic MCN and low soluble reagents. Furthermore, C–H oxidation and C–CN cleavage are proposed to be involved in this cascade process.

The synthesis of three tetrahydroxyindolizidines and one tetrahydroxypyrrolizidine related to natural hyacinthacines B and their biological evaluation as glycosidase inhibitors is reported. The target molecules were obtained through highly stereoselective cycloadditions between sugar-derived nitrone 6 and suitable chemoenzymatically prepared enantioenriched allylic and homoallylic alcohols. This allowed the installation of a methyl group at C5 – a common feature of many natural hyacinthacines – with high control over the stereoselectivity. The new compounds inhibit amyloglucosidase from Aspergillus niger and β-glucosidase from almonds. Compound 1 is a competitive inhibitor of amyloglucosidase and shows a fair selectivity towards this enzyme. The presence of C5-Me substitution in indolizidines 2 and 3 slightly diminishes the inhibitory activity towards amyloglucosidase whereas it improves the inhibitory properties towards β-glucosidase.

Cycloaddition between a carbohydrate-derived nitrone and suitable chemoenzymatically prepared enantioenriched allylic and homoallylic alcohols allowed the straightforward synthesis of three tetrahydroxyindolizidines and one tetrahydroxypyrrolizidine related to natural hyacinthacines B. They inhibit amyloglucosidase from Aspergillus niger and β-glucosidase from almonds.

An unprecedented olefination reaction of secondary amines with carbon nucleophiles has been developed through C–N/C–H functionalization under metal-free oxidative conditions. In the presence of a stoichiometric amount of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), a range of secondary N-alkylanilines smoothly underwent oxidative olefination with 2-alkylazaarenes, acetophenone, and malononitrile to give structurally diverse polysubstituted alkenes in moderate to excellent yields with excellent (E) selectivity. Preliminary mechanistic studies revealed that the oxidative olefination reaction proceeds through amine oxidation followed by imine olefination.

A range of secondary N-alkylanilines smoothly underwent DDQ-promoted oxidative olefination with 2-alkylazaarenes, acetophenone, and malononitrile to give structurally diverse alkenes in moderate to excellent yields with excellent (E) selectivity. Mechanistically, the reaction proceeds through amine oxidation followed by imine olefination (DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone).

An ester exchange reaction of β-butoxy-β-acyloxyvinyl-λ³-iodane with lithium bases (ROLi and nBuLi) efficiently generates highly labile monoester iodonium ylide at low temperature. The iodonium ylide generated in situ cleanly undergoes Darzens condensation with aromatic aldehydes to afford trans-epoxy ester selectively.

The reactivity of monoester iodonium ylide is investigated. Highly labile mono ester iodonium ylide generated in situ from β-butoxy-β-acyloxyvinyl-λ³-iodane through an ester exchange reaction cleanly undergoes Darzens-type condensation with aromatic aldehydes to afford trans-epoxy ester selectively.

Nitrogen-containing stereotriads, which are defined as compounds with three adjacent stereodefined carbon atoms, are common structural motifs in several biologically relevant compounds. The 1,3-diamino-2-ol motif in particular is an important pharmacophore for which there are limited stereoselective synthetic approaches. In this communication, we describe the aminohydroxylation of a series of bicyclic methylene-aziridines obtained from the aziridination of a series of homoallenic carbamates. The unusual electronic and steric features of these useful heterocyclic scaffolds render the Os-catalyzed aminohydroxylation of the exocyclic alkene highly regio- and stereoselective. Rearrangement of the proposed N,O-aminal intermediate to a 1,3-diamino-2-one is followed by reduction with NaBH₄ to deliver the desired 1,3-diamino-2-ols in good yields with high diastereomeric ratios.

Complex amine-containing stereotriads are recurring motifs in a number of bioactive and pharmacologically important molecules. The regio- and stereocontrolled aminohydroxylation of bicyclic methylene-aziridines can be followed by carbonyl reduction to deliver 1,3-diamino-2-ols in good yields with good diastereoselectivities (Ts = para-tolylsulfonyl, Bs = phenylsulfonyl, Boc = tert-butoxycarbonyl).

The group 10 metal complexes of β,β′-dioxoporphyrin monooxime 10M (M = Ni^II, Pd^II, Pt^II) are susceptible to a Beckmann rearrangement to produce the corresponding ring-expanded metallopyrazinoporphyrin imides 11M in good yields. These chromophores possess metallochlorin-like optical properties. Demetalation of the Ni^II complex furnishes the free-base porphyrinoid 11, which possesses a porphyrin-like optical spectrum. The monooximes are ultimately derived from meso-tetraphenylporphyrin, and the formal replacement of the porphyrin β,β′-double bond by an imide functionality is thus demonstrated. The imide functionality serves as a synthetic handle for further modification of the chromophore.

A Beckmann reaction of a porphyrindione monooxime is used to expand a pyrrole to a pyrazine imide moiety within the porphyrin and generate a new pyrrole-modified porphyrin-like compound that contains a six-membered heterocycle. The imide functionality can serve as a synthetic handle for further manipulations of the chromophore.

The reaction of unsubstitued camphanyl-piperazine 4 with ZnCl₂, phenylacetylene, and benzaldehyde in toluene gave the corresponding dipropargylamine (i.e., 15) with opposite configurations at the newly formed stereogenic centres, which, upon reaction with ZnI₂ resulted in the formation of a racemic mixture of 1,3-diphenyl allene in 45 % yield. N-Methylcamphanyl-piperazine regioisomer 5, prepared by selective N-methylation of the NH moiety attached to the stereogenic centre with (S)-configuration, upon reaction with ZnCl₂, phenylacetylene, and benzaldehyde in toluene, gave the corresponding propargylamine in 90 % yield, with an (S)-configuration at the newly formed stereogenic centre, and upon subsequent reaction with ZnI₂, this intermediate gave (R)-1,3-diphenyl allene in 52 % yield and with 96 % ee. Reaction of N-methylcamphanyl-piperazine isomer 5 with several 1-alkynes and aldehydes in the presence of ZnBr₂ gave the corresponding (R)-allenes in 40–75 % yield and 79–99 % ee. In contrast, regioisomeric N-methylcamphanyl-piperazine 6 reacted with ZnBr₂ to give the corresponding (S)-allenes in 38–71 % yield and with 79–99 % ee. The opposite chiral discriminating abilities of the two NH moieties in camphanyl-piperazines was confirmed by single-crystal X-ray analysis of the propargylamines formed. The results are discussed considering mechanisms involving the in situ formation of alkynylzinc halides, followed by diastereoselective addition to chiral iminium ion derivatives to give the corresponding propargylamines, and subsequent conversion to chiral allenes by an intramolecular 1,5-hydrogen shift.

A new method for the synthesis of both isomers of chiral 1,3-disubstituted allenes with enantiomeric purity up to 99 % ee, using selectively alkylated chiral camphanyl-piperazines, aldehydes, terminal alkynes, and ZnBr₂ has been developed.

A general strategy for the stereoselective total syntheses of cladospolides A, B, and C and iso-cladospolide B has been accomplished. The key steps provide easy access to the target molecules and include an alkyne-zipper reaction, a Sharpless asymmetric epoxidation/dihydroxylation, and a Yamaguchi macrolactonization. The feasibility of the alkyne-mediated approach to construct the required carbon framework as well as to create the diol functionality and the olefin geometry is successfully demonstrated.

A common alkyne-mediated approach to the total syntheses of cladospolides A, B, and C and iso-cladospolide B was accomplished by using an alkyne-zipper reaction, a Sharpless asymmetric epoxidation/dihydroxylation, and a Yamaguchi macrolactonization as the key steps.

Second-order reaction kinetics of known strain-promoted azide–alkyne cycloaddition (SPAAC) reactions were compared with theoretical data from a range of ab initio methods. This produced both detailed insights into the factors determining the reaction rates and two straightforward theoretical tools that can be used to predict a priori the reaction kinetics of novel cyclooctynes for strain-promoted cycloaddition reactions. Multiple structural and electronic effects contribute to the reactivity of various cyclooctynes. It is therefore hard to relate a physical or electronic property directly and independently to the reactivity of the cyclooctyne. However, we show that Hartree–Fock LUMO energies, which were acquired while calculating activation energies at the MP2 level of theory, correlate with second-order kinetic rate data and are therefore usable for reactivity predictions of cyclooctynes towards azides. Using this correlation, we developed a simple theoretical tool that can be used to predict the reaction kinetics of (novel) cyclooctynes for SPAAC reactions.

Activation energies, distortion energies, and TS conformational data were compared in a set of strained cyclooctynes in strain-promoted azide–alkyne cycloaddition (SPAAC) reactions. Only electronic effects could be accurately related to experimental rate data.

A novel methodology for the synthesis of S- and N-functionalized dithiocarbamates starting from cyclic sulfates, amines and carbon disulfide by using different protocols, including microwave assistance and a multicomponent variant, has been developed. The procedure is highly versatile, simple and efficient.

As an efficient route to dithiocarbamates, a simple and versatile method for preparing S- and N-functionalized dithiocarbamates starting for readily available cyclic sulfates and commercial amines under environmentally friendly conditions is reported.

Based on a previously developed method for the synthesis of epibatidine analogues, a series of new ionic liquids, based on the 7-azabicyclo[2.2.1]heptane skeleton, have been synthesized. The chemical and physical properties of the ionic liquids with bis(trifluoromethylsulfonyl)imide (Tf₂N) and dicyanamide [N(CN)₂] anions were investigated and they were found to exhibit very good electrochemical and thermal stabilities.

Ionic liquids with the cationic part based on the structure of epibatidine (a 7-azabicyclo[2.2.1] skeleton) have been prepared. The chemical and physical properties of these ionic liquids with dicyanamide and bis(trifluoromethylsulfonyl)imide anions were investigated and they were found to show very good electrochemical and thermal stability.

The regioselective aminoalkylation of indoles and related heterocycles with α-amido sulfones under basic conditions has been studied. The reaction that employed the MeMgBr/MgBr₂ system provided high yields of 3-(1-carbamoylalkyl)indoles. On the other hand, the reaction that used Cs₂CO₃ afforded 1-(1-carbamoylalkyl)indoles exclusively in high yields. The first reaction constitutes a switch of the leaving group of the α-amido sulfone in comparison to previously reported reactions between indoles and α-amido sulfones, which provided 3-(1-arylsulfonylalkyl)indoles. The second reaction constitutes a switch in the regioselectivity. The extensions of these C- and N-aminoalkylations starting from pyrroles and 7-azaindole have also been studied. Structurally diverse aminoalkylated indoles, pyrroles, and 7-azaindoles were obtained with excellent yield in most of the cases.

The regioselective aminoalkylation of indoles and heterocycles with α-amido sulfones under basic conditions is described. The reaction with MeMgBr/MgBr₂ gives 3-(1-carbamoylalkyl)indoles, whereas employing Cs₂CO₃ yields 1-(1-carbamoylalkyl)indoles. The first case presents a switch of the leaving group of the α-amido sulfone, whereas the second demonstrates a switch in the regioselectivity.

The requirement for new strategies for synthesizing five-membered carbocycles has driven an expansion in study of the Nazarov cyclization. This renewed interest in the reaction has led to the discovery of several interesting new methods for generating the pentadienyl cation intermediates central to the cyclization. Methods reviewed include carbon-heteroatom ionization, double bond functionalization, nucleophilic addition, or electrocyclic ring opening. Additional variations, such as iso- and imino-Nazarov cyclization, employ unconventional substrates to produce new pentacycles. Here we provide an overview of these unconventional, yet highly useful versions of the Nazarov cyclization.

Nazarov electrocyclization is a synthetic method for the preparation of functionalized five-membered rings, often in a stereospecific manner. This review highlights innovative strategies for gaining access to the key pentadienyl cation intermediates and illustrates how these new approaches have expanded the scope and utility of the reaction.

A series of metallodendrimers 9–11, as well as their corresponding ligands, were designed and synthesized. These materials integrate perylene as a functional core with <tpyRu^IItpy> termini; both chromophores are known for their photovoltaic properties. The products were fully characterized by a combination of ¹H NMR and ¹³C NMR spectroscopy, COSY, and MS. Their photophysical properties revealed a broad absorption spectrum with enhanced molar absorption coefficients corresponding to the increase in the number of <tpyRu^IItpy> units, which is indicative of their potential as candidates for light harvesting.

A family of functional materials bearing a perylene core and terpyridine branches, along with their Ru^II–bis(terpyridine) complexes, was designed and synthesized. Their structures were elucidated by NMR spectroscopy and MS. Their optical properties showed absorption spectra that ranged from 250 to 625 nm, which suggests their possible use as sensitizers for dye-sensitized solar cells.

The title compounds were synthesized by ruthenium-catalyzed ring-closing metathesis of N-tosyl-N-(ω-alkenyl)aminomethylvinyl phosphonates, which were obtained from N-(ω-alkenyl)-N-tosylamides. These compounds, in turn, were prepared from unsaturated alcohols through the Mitsunobu reaction. This methodology gives access to five- and six-membered ring compounds. Additionally, chiral phosphonates can be obtained easily.

Organocatalysis and ring-closing metathesis enable a two-step synthesis of azaheterocyclic vinylphosphonates, giving access to five- and six-membered ring compounds. The required (ω-alkenyl) p-toluenesulfonamides were obtained through the Mitsunobu reaction, which allows the synthesis of chiral phosphonates.

The cancer-cell-cytotoxicity-guided fractionation of the acetone extracts of two cultured marine-derived Streptomyces strains belonging to the MAR4 group yielded six new napyradiomycins, compounds A–F (1–6), together with three known compounds, napyradiomycins B2–B4 (7–9). Napyradiomycins 1–4 are new members of the napyradiomycin “C-type” meroterpenoids, which possess a linear monoterpene bridge between C-7 and C-10a. Compound 4 has an additional tetrahydropyran ring fused to the phenol moiety. Compounds 5–9 are related to the napyradiomycin “B-type” meroterpenoids. The structures of all new compounds were assigned by interpretation of 1D and 2D NMR, MS, and other spectroscopic data. The relative configurations were assigned based upon interpretation of ROESY 2D NMR experiments. The cytotoxicity of 1–9 against the human colon carcinoma cell line HCT-116 and their antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA) are presented.

The cancer-cell-cytotoxicity-guided fractionation of the acetone extracts of two cultured marine-derived Streptomyces strains yields six new napyradiomycins (1–6). Napyradiomycins 1–4 are new members of the napyradiomycin “C-type” meroterpenoids, which possess a linear monoterpene bridge between C-7 and C-10a. The cytotoxicity and antibacterial activities of 1–6 are presented.

The synthesis of heterobase-functionalized cyclopentene derivatives as valuable substrate for the introduction of suitable substituents through pericyclic reactions is reported. The structures of ene and 1,3-dipolar adducts are discussed, and the primary antiviral activities of some adenine derivatives are reported.

The synthesis of heterobase-functionalized cyclopentene derivatives as valuable substrates for the introduction of suitable substituents through pericyclic reactions is reported. The structures of ene and 1,3-dipolar adducts are discussed, and the primary antiviral activities of some adenine derivatives are reported.

The synthesis of (E)-2-cyano-3-(5′-piperidin-1-yl-2,2′-bithien-5-yl)acrylic acid, a novel amyloid aggregation fluorescent probe, is reported. This new probe is able to monitor soluble oligomeric aggregates after 24 h, at which time Thioflavin T emission, commonly used to monitor amyloid fibril formation, remains unchanged. Atomic force microscopy, native polyacrylamide gel electrophoresis, and dynamic light scattering confirm that the earlier stages of aggregation are prefibrillar oligomeric species not possessing the amyloid structure. This new molecular scaffold expands the toolbox of fluorescent probes for the identification of prefibrillar oligomers, which is needed in studies aimed at the early detection of the soluble toxic aggregates that characterize the so-called protein misfolding diseases.

(E)-2-Cyano-3-(5′-piperidin-1-yl-2,2′-bithien-5-yl)acrylic acid (p-TTCNAc) can be conveniently used as a fluorescent probe to identify prefibrillar oligomers of hen egg white lysozyme not detected by Thioflavin-T (ThT).

Whereas the reaction of 1,4-bis(2-bromoethyloxy)benzene (4) with paraformaldehyde in the presence of BF₃·Et₂O afforded exclusively the cyclopentameric pillar[5]arene derivative (5), both cyclopenta- and cyclohexameric macrocycles 5 and 6 were obtained when the reaction of 4 with paraformaldehyde was performed at 45 °C in CHCl₃ with FeCl₃ as the catalyst. Treatment of compounds 4–6 with sodium azide provided the corresponding polyazides, to which a cyanobiphenyl building block was subsequently grafted to generate model compound 1, pillar[5]arene 2, and pillar[6]arene 3, bearing two, ten and twelve mesomorphic subunits, respectively. The liquid-crystalline and thermal properties of the compounds were investigated by polarized optical microscopy (POM), differential scanning calorimetry (DSC), and X-ray diffraction (XRD). Comparison of the liquid-crystalline properties of macrocycles 2 and 3 with those of 1 revealed the strong influence of the macrocyclic pillar[n]arene core on the mesomorphic properties. Whereas only a monotropic mesophase was observed for 1, a broad enantiotropic mesophase was evidenced for both pillar[n]arene derivatives.

Pillar[n]arene (n = 5 or 6) derivatives substituted with peripheral mesogenic moieties gave rise to an enantiotropic smectic A phase over a very broad temperature range, whereas only a monotropic mesophase was observed for the corresponding constitutive acyclic monomeric subunit.

Simple tripeptides are shown here to be versatile ligands for iridium-catalyzed transfer hydrogenations affording large acceleration effects. A water-soluble iridium complex with Gly-Gly-Phe, for example, catalyzes the reduction of diverse ketones, aldehydes, and imines by formate with turnover frequencies rivaling or outperforming those of established ligand systems. Regioselective reduction of coenzyme NAD⁺ to NADH illustrates the potential utility of this system for biotechnological applications. Because peptides are genetically encodable, they represent an attractive class of foldamer ligands for creating artificial metalloenzymes.

Simple tripeptides are shown to be effective ligands for iridium-catalyzed transfer hydrogenations. Peptide–iridium complexes efficiently reduce ketones, aldehydes, imines, and NAD⁺ under mild conditions in aqueous buffer. As genetically encodable foldamers, peptides are attractive ligands for the construction of artificial metalloenzymes for diverse biotechnological applications.

Formal cycloaddition-retroelectrocyclization (CA-RE) reactions between electron-donor-activated alkynes and electron-poor alkenes yielding cyanobuta-1,3-dienes have recently attracted increasing interest. The transformation has been subjected to a fundamental investigation of the relative degrees of alkyne activation by organic and metallorganic donor substituents by using platinum(II) σ-acetylides as model substrates and studying their behavior towards the cyano carbons TCNE and TCNQ. Various cyanobutadienes were obtained in good to excellent yields and four trends in reactivity were discerned: 1) The presence of an anilino substituent clearly dominates the regioselectivity of the TCNQ addition. 2) In the absence of an organodonor, the regioselectivity is inverted. 3) When platinum(II) complexes of buta-1,3-diynes are used, the addition always takes place at the triple bond distal to the metal center. 4) In general, trans-bis-acetylides are more reactive than the corresponding cis complexes. The structural parameters of the CA-RE adducts were investigated by X-ray crystallography and their optical properties by UV/Vis spectroscopy, giving further insights into the structural trends and degree of intramolecular charge transfer. These fundamental investigations may enable the synthesis of new Pt-based molecular dyads in which the effect of regioselectivity on photoinduced charge separation can be studied.

Donor-activated triple bonds act as substrates for cycloaddition-retroelectrocyclization reactions with TCNE or TCNQ to give cyanobutadienes. Herein we showcase the activation ability of two classes of donors: organic amines and platinum(II) centers directly bound to the acetylenic moieties and compare them directly for the first time.

Four new cucurbiturils Cy_nCB[6] containing n (n = 1, 2, 4, 5) cyclohexyl equatorial units have been synthesized to complete the family of known Cy₃CB[6] and Cy₆CB[6] derivatives. A new CB[6] member bearing a propanediurea unit has also been prepared. The CB[6] derivatives show better solubility in pure water than native CB[6]. One cyclohexyl unit is sufficient to enhance the solubility in water by a factor of 170 with respect to CB[6], and Cy₆CB[6] is around 30 times more soluble than Cy₁CB[6]. The cyclohexane moieties, by limiting or impeding the formation of intermolecular C–H···O hydrogen bonds, may explain this increase in solubility. The effect of modification of the molecular shape on the solubility was assessed by liquid-state NMR spectroscopy and DFT calculations.

New molecules derived from cucurbit[6]uril with either a propanediurea unit or cyclohexane moieties have been synthesized. Their solubility in pure water increased with the number of these nonclassical units. This can be explained in terms of changes in intermolecular C–H···O hydrogen bonding rather than in the molecular shape.

Cold-adapted bacteria are microorganisms that thrive at very low temperatures in permanently cold environments (0–10 °C). Their ability to survive under these harsh conditions is the result of molecular evolution and adaptations, which include the structural modification of the phospholipid membrane. To give insight into the role of the membrane in the mechanisms of adaptation to low temperature, the characterization of other cell-wall components is necessary. Among these components, the lipopolysaccharides are complex amphiphilic macromolecules embedded in the outer leaflet of the external membrane, of which they are the major constituents. The cold-adapted Colwellia psychrerythraea 34H bacterium, living in deep sea and Arctic and Antarctic sea ice, was cultivated at 4 °C. The lipooligosaccharide (LOS) was isolated and analysed by means of chemical analysis. Then it was degraded either by mild hydrazinolysis (O-deacylation) or hot KOH (4 M; N-deacylation). Both products were investigated in detail by ¹H and ¹³C NMR spectroscopy and by ESI FT-ICR mass spectrometry. The oligosaccharide portion consists of a unique and very short species with the following general structure: α-L-Col-(1→2)-α-D-GalA-(1→2)-α-D-Man-[3-P-D-Gro]-(1→5)-α-D-Kdo-4-P-Lipid-A.

The structural characterization of the lipooligosaccharide from the steno-psychrophilic bacterium Colwellia psychrerythraea strain 34H has been achieved by means of chemical analysis, mass spectrometry, and NMR spectroscopy experiments. The data revealed a very short, negatively charged, and unique oligosaccharide, lacking heptose residues.

The first examples of phosphane-catalyzed [3+2] annulation of allenoates to 6-alkylidenepenicillanates leading to chiral spirocyclopentenyl-β-lactams are reported. The synthesis of this new type of β-lactams involved the generation of either two or three consecutive stereogenic centers, including a quaternary chiral center. Although the reported methodology is highly diastereoselective, the regioselectivity is dependent on the nature of the methylenepenicillanate derivative and on the nature of the allenoate γ-substituent.

The first examples of phosphane-catalyzed [3+2] annulation of allenoates to 6-alkylidenepenicillanates leading to chiral spirocyclopentenyl-β-lactams are reported. The process involves the generation of either two or three consecutive stereogenic centers, including a quaternary chiral center.

The selective synthesis of amines continues to be of importance because of their application in the bulk and fine chemical industries. Herein, domino ruthenium-catalyzed transfer hydrogenation of nitriles with subsequent N-monoalkylation by using alcohols is described. With this novel approach, various nitriles were reductively N-monoalkylated in excellent yields.

A simple method for the synthesis of secondary amines starting directly from nitriles by using a ruthenium catalyst is described. With this novel domino system, various nitriles were reduced and subsequently N-monoalkylated in excellent yields (up to 99 %). In addition to isopropanol, other alcohols were also used as a reductant and N-monoalkylation reagent.

A series of 9-(fluoren-2-yl)anthracene derivatives bearing either thiophene (FATh), triphenylamine (FAT and FATT) or pyrene (FATP) moieties as substituents have been designed, synthesized, and characterized as non-doped blue emitters for organic light-emitting diodes (OLEDs). Their optical, electrochemical and thermal properties have been investigated, and their molecular structure-property relationships were evaluated. All FAT, FATT and FATP compounds possess combined blue-light-emitting and hole-transporting characteristics, and showed stable amorphous states with high fluorescence quantum yields in solution (up to 89 %) and strong luminance in the OLED devices, whereas FATh showed poor photoluminescent and electroluminescent properties. Efficient, non-doped blue and Alq3-based green OLEDs were fabricated and characterized. The blue and green devices with maximum luminance efficiencies and CIE coordinates of 3.17 cd A^–1 and (0.13, 0.14), and 3.81 cd A^–1 and (0.28, 0.50) were achieved, respectively, with FATT having 4-{bis[4′-(diphenylamino)biphenyl-4-yl]amino}phenyl substituents as emitting layer and hole-transporting layer, respectively. These devices also showed considerably low turn-on voltages of 3.0 and 2.6 V, respectively.

New 9-(fluoren-2-yl)anthracene derivatives with combined blue-light-emitting and hole-transporting characteristics have been developed that exist in a stable amorphous state and deliver high fluorescence quantum yields.

A radical C–C bond formation between olefins and alcohols proceeded efficiently by simple light irradiation at room temperature. The reaction proceeded in the presence of commercially available tBuOOtBu without using the harmful elements and/or compounds that have an unpleasant smell that are often used in conventional radical reactions. In addition, the reaction did not require photosensitizers or photocatalysts, which eliminated the time-consuming separation of sensitizers after the reaction, or the synthesis of photocatalysts as reported in previous procedures.

A radical C–C bond formation between olefins and alcohols proceeded efficiently by simple light irradiation at room temperature without using the harmful elements often used in conventional radical reactions.

Here we present folding-associated aggregation propensity of three Trp-cage foldamers: E0 (20 aa), E5 (25 aa) and E10 (30 aa), models of different sizes but comparable molecular properties. Electronic circular dichroism (ECD), vibrational circular dichroism (VCD) and FT-IR spectroscopic measurements were used to monitor their concentration-dependent, heat-induced (5 °C → 65 °C) “α→β” fold transition. The ECD curves of E0 display an ensemble of highly dynamic structures. ECD of both E5 and E10 foldamers show the expected Trp-cage fold, dominated by their α-helical properties. No sign of β-structures was revealed by ECD at any conditions (5 °C < T < 65 °C, 5 < pH < 7, c ≈ 30 μM) for any of these miniproteins. However, at higher concentration (c ≈ 1–30 mM) both VCD and FT-IR spectral features of E5 as well as E10 resemble that of a β-strand (ca. 1615 cm^–1), accompanied with “free β-edges”, or native β-sheets (ca. 1635 cm^–1). E5 at lower concentrations (c ≈ 1–3 mM), and E10 at higher concentration (c ≈ 30 mM) display the α→native-β→β-sheet folding transitions, monitored by the characteristic C=O vibrational normal mode frequency shift as follows: ca. 1650 cm^–1 → ca. 1635 cm^–1 → ca. 1615 cm^–1, respectively. The latter folding path is irreversible. The shortest polypeptide E0 has an “unordered” fold, while E10 presents the most tightly packed Trp-cage 3D-structure. We have found that both high dynamicity and/or tight molecular core packing are different in nature, but common in efficacy in preventing the polypeptide backbone chain against self-aggregation. However, E5 is intermediate in size and stability, and thus among these three polypeptides it is the quickest to aggregate. The present molecular triad, E0, E5 and E10, serves as a good example of larger globular proteins for which aggregation and amyloid fiber-like nanoparticle formations are often associated with Alzheimer's, Creutzfeldt–Jakob, or prion diseases.

Optical spectroscopic studies of the small, well-folded peptide foldamer, Trp-cage miniprotein. Investigation of stability-associated aggregation properties of three Trp-cage foldamers.

One of the big challenges in the organic chemistry of functionalized carbon nanotubes (CNTs) is the characterization of their structure together with their physicochemical properties. In this work, we report the utilization of an acridine-derived Zn^II-cyclen complex as a multidentate ligand for recognizing thymidine-derived multiwalled carbon nanotube derivatives (Td-MWCNTs). The effectiveness of the Zn^II-cyclen recognition has been confirmed through a combination of analytical techniques such as the Kaiser test, TGA-MS, IR, X-ray photoemission spectroscopy, TEM, UV/Vis absorption, and fluorescence spectroscopy. Taken together, the different characterization techniques have unambiguously shown the 1:1 recognition of the nucleoside by a Zn^II-cyclen complex, allowing an accurate estimation of the Td moieties present on the CNTs surface.

The Zn^II-cyclen macrocycle is revealed to be an efficient and selective molecular probe for tagging thymidine (Td) nucleoside functionalities covalently linked to multiwalled carbon nanotubes (MWCNTs).

This article details the characteristic conformational features of the Ant-Pro reverse turn ― a folded pseudo β-turn motif that displays a closed nine-membered-ring hydrogen-bonded network involving just two amino acid residues, namely anthranilic acid (Ant; a constrained β-amino acid), and proline (Pro; a constrained α-amino acid). The results from the extensive investigation of ten crystal structures and their NMR conformations in the solution state provide a clear idea about the conformational characteristics of the Ant-Pro reverse turn. The Ant and Pro residues, which form the turn segment, maintain a perfect antiperiplanar orientation throughout, leaving little possibility for the formation of the otherwise possible six-membered hydrogen-bonding that requires a coplanar disposition of the two amino acid residues, as clearly evident from investigation of several crystal structures. The closed hydrogen-bonded network observed in the Ant-Pro reverse turn motif, formed in the forward direction of the sequence (1→2 amino acid interactions) involving only two amino acid residues, is in stark contrast to the native β-turns that involve four residues to form hydrogen-bonded network featuring backward 1←4 amino acid interactions. The readily available two-residue Ant-Pro motif raises the possibility of a practical utility, particularly in the application of rigidifying flexible peptide backbones by inserting the robust Ant-Pro reverse turn motifs into their backbone.

Characteristic conformational features of the Ant-Pro reverse turn ― a folded pseudo β-turn motif with a closed nine-membered-ring H-bonded network involving just two amino acid residues ― are described. The results were obtained from the investigation of ten crystal structures and their NMR conformations in the solution state.

An efficient synthesis of 5-organotellanyl-1H-1,2,3-triazole compounds was accomplished through [3+2] cycloaddition reaction of organic azides and (organotellanyl)alkynes. Additionally, 5-organotellanyl-1H-1,2,3-triazoles were readily functionalized at the 5-position by using a Sonogashira cross-coupling reaction, leading to highly functionalised triazoles. The regiochemistry of the products was assessed by two-dimensional NMR spectroscopic experiments and X-ray crystallography.

An efficient synthesis of 5-organotellanyl-1H-1,2,3-triazole compounds through [3+2] cycloaddition reaction of organic azides and (organotellanyl)alkynes is presented. The 5-organotellanyl-1H-1,2,3-triazoles were readily functionalized at the 5-position to give highly functionalized triazoles.

(1R,2S)-2-Aminocyclohexanecarboxylic acid (cis-ACHC) is a preorganized β-amino acid. cis-ACHC favors two conformations that feature gauche conformations about the C_α–C_β bond with torsion angles of opposite signs. The diastereomeric β-amino acid trans-ACHC has been widely studied as a foldamer building block, but cis-ACHC has received less attention in this regard. We examined the conformational behaviour of three types of oligomer: (1) homooligomers of cis-ACHC, (2) β-peptides in which cis-ACHC and β³h-Ala alternate, and (3) 1:1 α/β-peptides in which cis-ACHC and Ala alternate. Two-dimensional NMR experiments suggest that all three types of oligomer adopt extended conformations rather than folded conformations in solution. Two crystal structures of oligomers that contain cis-ACHC residues, a cis-ACHC dimer and an α/β-peptide tetramer, show extended conformations in which the cis-ACHC residues contain six-membered-ring C=O···H–N hydrogen bonds.

Three types of peptide oligomers that contain cis-2-aminocyclohexanecarboxylic acid (cis-ACHC) were analyzed by two-dimensional NMR spectroscopy and X-ray crystallography. Folded conformations do not appear to be populated in solution. Crystallographic data reveal extended confomations with specific preferences for cis-ACHC residues.

This paper describes the solvent-assisted addition of trimethylsilyl cyanide (TMSCN) to cyclic α-fluorinated ketones. In DMF, this method gives TMS-protected cyanohydrins in good yields (70–95 %) and with good selectivities (dr up to 22:1), and the products are readily reduced to the corresponding fluorinated 1,2-amino alcohols.

A method for the trimethylsilyl cyanide (TMSCN) addition to α-fluoro ketones has been developed, giving the nitrile products in high yields and with good to modest stereoselectivities. TMSCN is activated in strongly electron-donating solvents, such as DMF, to produce the fluorinated TMS-protected cyanohydrin in yields of up to 95 % and diastereoselectivities as high as 22:1.

By using a phosphane as an organocatalyst, an efficient synthesis of benzo-fused cyclic sulfamidate heterocycles has been developed through a cycloaddition reaction of allenoate and cyclic imines including cyclic trifluoromethyl ketimine, which gave high yields (71–97 %). The reaction could also be conveniently performed on a gram scale. Furthermore, some simple transformations of the sulfamidate heterocycle products have been disclosed to obtain functional amines. An asymmetric variant of this reaction was also tried by screening several commercially available chiral phosphane ligands as organocatalysts, and up to 36 % ee was achieved.

Benzo-fused cyclic sulfamidate heterocycles have been synthesized in 71–97 % yields through a cycloaddition reaction of allenoate with cyclic imines (various aldimines and a trifluoromethyl ketimine) by using PPh₃ as organocatalyst. After screening several commercially available chiral phosphanes, up to 36 % ee was obtained with (R)-H₈-BINAP.

Tautomerism in the [1,2,4]triazolo[3,2-c][1,2,4]triazole fused aromatic system has been investigated by single-crystal X-ray analysis, UV/Vis spectroscopy and theoretical calculations on selected new heterobicycle derivatives. The reactions of 3,4-diamino-1,2,4-triazoles with acyl chlorides or acetic anhydride in pyridine at reflux led to ring closure and the fused aromatic system was obtained as the secondary amide at N2 instead of at N5 as previously reported in the literature. For the [1,2,4]triazolo[3,2-c][1,2,4]triazole system, three different tautomers can be present. Crystal structure analysis showed the presence of only one tautomer or, depending on the packing, a mixture of two; theoretical calculations supported this finding, predicting that for all the investigated compounds one tautomer is energetically disfavoured with respect to the other two. The electronic absorption spectra of some compounds show a marked solvent dependence, which has been interpreted, with the help of theoretical calculations, in terms of acid/base equilibria, which are critically dependent upon the substituents at the heterobicycle.

[1,2,4]Triazolo[3,2-c][1,2,4]triazole has three tautomers: 2H, 3H and 5H. It is shown that the most stable tautomer is 2H, tautomer 3H has intermediate energy and the 5H has the highest energy. This compound provides a striking counter-example of the generally held view that the organic conjugated structure with the highest number of alternating single and double bonds is the most stable.

There is a significant unmet need for new antimicrobial agents that can address antimicrobial resistance. One promising group of antimicrobials is the antimicrobial peptides (AMPs) and their synthetic mimics. In particular, synthetic sequence-specific oligomers of N-substituted glycine, termed “peptoids”, have been found to show potent antimicrobial activity against bacterial pathogens in vitro and can act against the emergence of antimicrobial resistance. In this study, we evaluate the antimicrobial activity of cyclic peptoid oligomers against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA). The presence of the macrocyclic constraints can enforce a globally amphiphilic organization of the peptoid side-chains. Several of these new amphiphilic compounds show potent and selective antimicrobial activity. Electron microscopy experiments demonstrate that the peptoids target and damage the MRSA cytoplasmic membrane through the formation of pores. These results substantiate the potential of peptoids as antimicrobial therapeutic agents for the treatment of S. aureus infections.

Macrocyclic peptoid oligomers that organize into globally amphiphilic faces show potent antimicrobial activity against clinical isolates of methicillin-resistant Staphylococcus aureus (MRSA) and disrupt the bacterial cell surface, as shown by scanning electron microscopy. Scale bar: 300 nm.

Current applications of porphyrins in medicine and optics, such as photodynamic therapy or nonlinear absorption, increasingly require the use of far-red absorbing dyes. Modification of the porphyrin structure to accommodate these conditions can be achieved by extending the conjugation of the porphyrin π system, which causes a bathochromic shift in the absorption spectrum. Thus, conjugated porphyrin oligomers have found widespread use. However, past synthetic strategies have mainly targeted symmetric porphyrin dimers, trimers, and oligomers which limit the practical use of such chromophores. To further extend the absorption profile, a series of symmetric and unsymmetric dimeric and oligomeric porphyrin β–β, meso–meso, β′–β′ triply fused systems were synthesized by oxidative coupling methods. This required an analysis and optimization of the various synthetic strategies. These arrays exhibit a dramatic bathochromic shift into the near-infrared region and many display absorption at wavelengths greater than 1050 nm. Additionally, post-fusing chemical transformations, namely, organolithium, cycloaddition, and transition-metal-catalyzed reactions, at the meso and β positions enable the fine-tuning of such arrays to enhance the bathochromic shift and their potential optical applications.

A library of symmetric and unsymmetric singly linked and triply fused porphyrin dimers are synthesized in moderate to very good yields. A variety of functional groups are tolerated. Numerous synthetic strategies, incorporating oxidative radical coupling and organolithium and palladium-catalyzed coupling methods, are utilized.

A one-pot protocol for the synthesis of indole-based annulated polyheterocycles involving consecutive 7-endo-trig and electrophilic 6-endo-dig cyclizations is described. The reaction proceeds initially through annulation of 5-methoxyindole, 2-amino benzyl alcohol and 2-alkynylbenzaldehyde in a three-component tandem manner to form benzazepino-indole, which then undergoes a second consecutive ring closure through intramolecular hydroamination to yield isoquinolino-benzazepino-indoles hitherto not reported in the literature.

A one-pot three-component tandem reaction with a subsequent intramolecular hydroamination reaction was applied to generate libraries of benzazepino-indole and isoquinolino-benzazepino-indole derivatives.

A general procedure for the synthesis of aryl thioethers and aryl selenides in one-pot through sequential iridium-catalyzed C–H borylation and copper-promoted C–S and C–Se bond formation is described. Functional groups including chloro, nitro, fluoro, trifluoromethyl, and nitrogen-containing heterocycles were all tolerated under the reaction conditions. Importantly, not only aryl thiols and selenides but also their alkyl analogs were suitable coupling partners, and the products were obtained in good yields with high meta regioselectivity.

Aryl thioethers and selenides were prepared in good yields with high meta regioselectivity through sequential Ir-catalyzed C–H borylation and Cu-promoted C–S and C–Se bond formation in one pot. A wide range of functional groups were tolerated under the reaction conditions. In addition to aryl thiols and selenides, alkyl thiols and selenides were also suitable coupling partners in this reaction.

Pyrrolizidine, indolizidine, and pyrrolo[1,2-a]azepine substructures are present in a large number of naturally occurring azabicyclic compounds, which are currently of special interest because of their biological activities. To obtain this class of compounds, we envisioned a ring-rearrangement metathesis (RRM) process of 7-azanorbornene systems that incorporates several exocyclic olefin patterns at the nitrogen position. By using this methodology, we have synthesized a set of new 1-azabicyclo[n.3.0]alkenones, which include derivatives of pyrrolam. In all cases, only one regioisomer was obtained. Moreover, new spiro compounds with tricyclic structures have been synthesized by using a domino metathesis process that involves a ring-opening/ring-closing/ring-closing metathesis (ROM/RCM/RCM) sequence.

A new synthetic strategy for nitrogen heterocycles was developed that incorporates fused-ring systems and takes advantage of a stereodefined ring-rearrangement metathesis process of substituted 7-azanorbornenes as the stereocontrolled key step. A set of new 1-azabicyclo[n.3.0]alkenones (n = 3, 4, and 5) that include new analogues of pyrrolam were prepared by using this methodology.

Two carbene-based ligands have been attached to perbenzylated and permethylated cyclodextrins. Their palladium complexes were synthesized, characterized and used as catalysts in Suzuki–Miyaura coupling reactions both in ethanol and water.

Two carbene-based ligands have been attached to perbenzylated and permethylated cyclodextrins. Their palladium complexes were synthesized, characterized and used as catalysts in Suzuki–Miyaura coupling reactions both in ethanol and water.

Three series of new γ-peptides have been synthesized by starting from conveniently protected cis-3-amino-2,2-dimethylcyclobutane-1-carboxylic acid derivatives. The first series is constructed with only one enantiomer of this γ-amino acid, whereas in the second one both enantiomeric cyclobutane residues are joined in alternating fashion. The high degrees of rigidity in these γ-peptides induce the adoption of extended but sterically constrained conformations in both cases. The third series is the product of alternation of a cyclobutane residue with linear γ-aminobutyric acid (GABA). Conformational bias in these three systems accounts for the cyclobutane being a major disrupting factor to the formation of strong intramolecular hydrogen bonds, leading to extended conformations. In contrast, investigation of cyclobutane/GABA hybrid γ-peptides of a fourth series, in which the carbocyclic moiety is not a part of the polyamide skeleton but acts as a chiral polyfunctional platform, reveals that these peptides are able to produce intramolecular hydrogen bonds leading to well defined folded conformations.

Extended but constrained conformations are preferred when a chiral cyclobutane moiety forms part of the backbone in different polycyclobutane γ-peptides. Nevertheless, strong hydrogen bonds promoting folded conformations are produced in hybrid peptides when the carbocycle is not part of the main polyamide skeleton but acts as a chiral branched platform providing functionalized side chains.

Supramolecular synthesis, the “bottom-up” construction of higher-order structures from monomeric building blocks, represents a flexible approach for the generation of multivalent materials. Here, monovalent building blocks decorated with a single bioactive ligand were synthesized. In water, these supramolecular elements self-assemble into columnar polymers that display multiple ligands. The supramolecular effect on the binding affinity was evaluated by using an enzyme-linked lectin assay, and the self-assembled architecture exhibited a stronger inhibitory power than that of the monovalent bioactive ligand. This so-called self-assembling multivalency enables the rapid and flexible generation of multivalent polymers from monovalent building blocks.

The supramolecular multivalency of discotic molecules, which feature either a single or three mannose units and self-assemble into columnar polymers, is evaluated. The binding affinity of the multivalent supramolecular polymers is enhanced compared to that of the monovalent bioactive ligand. Additional decoration with three mannose ligands does not further contribute to the binding.

Peptidic foldamers are known to exhibit increased diversity in the periodic secondary-structure space in comparison with their natural counterparts, but their higher-order self-organization has been studied less thoroughly. In theory, large-diameter peptide foldamer helices have the capability of self-recognition through axial helix–helix interactions (e.g., head-to-tail), but this phenomenon has previously been observed in only one instance. In this article we report on the discovery of the largest-diameter β-peptidic mixed helix to date, the H18/20_P helix. Its formation is solvent-dependent and its folding occurs cooperatively through head-to-tail self-assembly in solution. These findings suggest that axial helix–helix interactions can serve as a new mode for the formation of tertiary/quaternary structures for peptide foldamers, which also show higher-order structural diversity than natural proteins.

The discovery of a large-diameter β-peptidic foldamer mixed helix is reported. The formation of the β-H18/20_P helix is solvent- and concentration-dependent, and occurs by a head-to-tail self-assembly process in solution.

A series of dinuclear chloride-binding foldamers – (TEA)₂[L¹Cl₂]·Et₂O (1), (TEA)₂[L²Cl₂] (2), (TBA)₂[L³Cl₂] (3), (TBA)₂[L⁴Cl₂] (4), [K(18-crown-6)]₂[L⁴Cl₂]·H₂O (5), and (TBA)₂[L⁵Cl₂]·H₂O (6) – have been synthesized from naphthyl- and anthracenyl-decorated oligoureas (tetrakisurea to hexakisurea, L¹–L⁵). In the crystal structures of 1–6, the oligoureas adopt helical conformations and two chloride anions are bound inside by the urea groups. The solution binding properties of L¹–L⁵ toward chloride ion were investigated by ¹H NMR and fluorescence spectroscopy. Upon binding of the anions, characteristic downfield shifts of the NH signals and enhanced fluorescent emission relative to the free ligands were observed. In DMSO solution, the ligands each display a 1:1 binding ratio to chloride, with association constants of K = 1.16–7.58 × 10² M^–1, which contrasts with the 1:2 (host to guest) binding mode in the crystal structures. However, the formation of dinuclear foldamers in the less polar solvent CHCl₃ was indicated by the HRMS (ESI) spectra.

A series of dinuclear chloride-binding foldamers have been synthesized from naphthyl- and anthracenyl-decorated, ortho-phenylene-bridged oligoureas (tetrakisurea to hexakisurea).

Replacement of a peptide bond with its thioamide surrogate is a classical method for the generation of a peptidomimetic with altered spectroscopic, conformational, physicochemical, and biological properties. In this context, we synthesized short series of terminally protected homo-α-oligopeptides based on the α-amino acids Gly, Ala, and Nle, as well as their corresponding fully thioamidated analogues. For the first time, the preparation of the latter compounds was achieved in single-step fashion through direct thionation of their oxygenated precursors. Using X-ray diffraction analysis and NMR spectroscopy we were also able to confirm that the thioamidated α-amino acid residues can easily adopt either folded or fully extended conformations.

Short series of terminally protected, fully thioamidated, homo-α-peptides were synthesized. For the first time, their preparation was achieved in single-step fashion through direct thionation of their oxygenated precursors. Conformation analysis confirms that the thioamidated α-amino acid residues can easily adopt either folded or fully extended conformations.

The Masuda borylation/Suzuki arylation (MBSA) sequence starting from N-protected 3-iodoindoles has successfully been extended to the coupling of five-membered heterocycles and indoles in the arylation step, which could not be achieved with previously developed MBSA methods. By this approach the one-pot nature of the method as well as the use of a simple catalyst system has been retained. The applicability of the method has been demonstrated by the facile synthesis of camalexins and 3,3′-biindoles, compounds of special interest due to their pronounced antifungal, antimicrobial and cytotoxic activities.

The Masuda borylation/Suzuki arylation sequence furnishes in a concise one-pot manner camalexins and 3,3′-biindoles, compounds that show pronounced antifungal, antimicrobial, and cytotoxic activities.

Cyclic γ-amino acids are molecular building blocks of great interest in peptide and foldamer chemistry, as they allow the preparation of new structures that are not found in Nature. In this paper, we describe the synthesis of cyclic γ-amino acids that have a cis relationship between the amino and the carboxylic acid groups. This arrangement, in most cases, induces the resulting peptides to adopt a flat conformation, which makes them appropriate for the design of foldamers that adopt β-sheet-type structures.

We describe the synthesis of cyclic γ-amino acids that have a cis relationship between the amino and the carboxylic acid groups. This makes them suitable for the design of foldamers that adopt β-sheet-type structures.

The efficient and asymmetric synthesis of two analogues of meiogynin A, a natural sesquiterpenoid dimer that was recently isolated by our group, is reported. The key reaction was a highly selective intermolecular Diels–Alder reaction between an aromatic triene and two chiral dienes. This convergent synthesis maximizes the atom economy concept, as the expected compounds were obtained in only eight steps without any protecting groups.

Two analogues of meiogynin A, a natural sesquiterpenoid dimer that interacts with a family of antiapoptotic proteins, were synthesized. They were obtained in only eight steps with very good selectivity, without any protection steps.

The cover picture showstwo enantiomerically pure [6]helicene dimers. One is linked by an ethane-1,2-diyl moiety, whereas the other features an ethene-1,2-diyl bridge connecting the helicenes electronically. Intriguingly, the peaks of the electronic circular dichroism (ECD) traces of the latter feature values almost three times larger compared to those of the former, which exhibits values in the same order of magnitude as monomeric [6]helicenes. Synthesis, extensive analysis of the chiroptical properties (both experimentally and computationally), and attempts to convert the stilbenoid [6]helicene dimer into [13]helicene are discussed in the article by F. Diederich et al. on page 3223 ff.

Ammonia (NH₃) is a cheap, abundant, and readily available nitrogen source, being one of the chemicals produced in the greatest quantities. Whereas ammonia is utilized mainly as a feedstock for the production of fertilizers, it is also employed in industry as a component of various nitrogen-containing compounds. In metal catalysis, in contrast, ammonia has been used only with limited success, due to several difficulties such as generation of stable Lewis acid-base adducts, facile ligand exchange for ammonia in active metal complexes, a propensity towards undesired second transformations of initially formed species, and the requirement for special equipment to run the reactions. Despite these obstacles, the direct use of ammonia in catalysis has continuously attracted great interest, leading recently to significant progress. Whereas liquid or gaseous ammonia were most commonly employed in the past, under harsh conditions, notable catalytic reactions using easy-to-handle ammonium salts under milder and more convenient conditions have now been developed. In this review we briefly describe the most recent examples of transition-metal-catalyzed reactions using ammonia or ammonium salts.

Although ammonia (NH₃) is a cheap, abundant, and readily available nitrogen source, it has rarely been used in transition-metal catalysis, due to several obstacles. However, significant advances in the metal-mediated utilization of ammonia have been made recently. This review presents the most recent examples in metal-mediated amination and other relevant reactions with ammonia or ammonium salts.

The synthesis of four new bis(oxazoline) (BOX) derivatives bearing two additional coordination sites at the 4,4′-positions is presented. As these BOX scaffolds contain an unsubstituted methylene bridge, they should be capable of forming neutral metal complexes. Thus, these molecules are very interesting ligands for bifunctional catalysis. In addition, one BOX scaffold bearing two azide moieties was successfully employed in copper-free 1,3-dipolar cycloaddition reactions. The resulting products have yet again high ligand potential.

The efficient synthesis of bis(oxazoline) (BOX) derivatives bearing two additional coordination sites at the 4,4′-positions is presented. As these BOX scaffolds contain an unsubstituted methylene bridge, they should be capable of forming neutral metal complexes. Thus, these molecules are very interesting ligands for bifunctional catalysis.

A modified Feist–Bénary furan synthesis has been developed that involves a lithium aldol reaction between a methyl ketone and an α-chloroaldehyde followed by a thermally induced tetrahydrofuran formation/dehydration sequence and affords 2,5-disubstituted furans in good overall yield. This process is demonstrated on multigram scale and is amenable to the production of symmetric or asymmetric furans that incorporate a range of substituents (e.g., aryl, tert-butyl, ferrocenyl).

A modified Feist–Bénary furan synthesis has been developed that involves a lithium aldol reaction of an α-chloroaldehyde followed by a thermally induced tetrahydrofuran formation/dehydration sequence. This process provides access to a range of 2,5-disubstituted furans and is demonstrated on multigram scale.

We synthesized stilbenoid (E)-(P,P)- and (E)-(M,M)-[6]helicene dimers in enantiomerically pure form as part of a program aimed at the exploration of new strategies for the synthesis of large helicenes. The [2+2+2] cyclotrimerization of suitable triynes, reported by Starý and co-workers, was applied for the preparation of a racemic 2-hydroxymethylated [6]helicene precursor, which was conveniently resolved by HPLC on a chiral stationary phase. Two optically active helicenes were subsequently connected to the stilbenoid dimer by olefin metathesis. Electronic circular dichroism (ECD) studies of the stilbenoid ethen-1,2-diyl-linked dimer revealed bathochromically shifted ECD bands with exceptionally large Cotton effects relative to those of the monomeric [6]helicenes or to that of a dimeric [6]helicene with a saturated ethan-1,2-diyl linker. These comparative studies, complemented by computational investigations, show that the pronounced chiroptical properties of the stilbenoid dimer originate from π-conjugation between the two [6]helicene moieties and from the rigidity that results from conjugation. All attempts to form (P)-[13]helicene by photocyclodehydrogenation of the stilbenoid (P,P)-dimer were unsuccessful.

Enantiomerically pure [6]helicene dimers with a π-conjugated bridge between the two helices feature enhanced Cotton effects in the electronic circular dichroism spectra if compared to the spectra of [6]helicenes or dimers featuring a saturated C₂ bridge. Despite predictions, the conjugated dimer could not be converted into a targeted [13]helicene, presumably as a result of steric hindrance.

Three bisannulation strategies have been used to rapidly construct pentacyclic benzo-fused pyrrolo[4,3,2-mn]acridines, similar to several biologically active natural products. The key steps involve Michael substitution of 2,3-dichloro-1,4-naphthoquinone with o-nitrophenylacetic acid derivatives, followed by domino amino-Michael substitutions/cyclisations. The most efficient of these syntheses provided a model compound (1) including the ABCD ring-system of alpkinidine, in just three steps and 55 % overall yield.

An annulation strategy involving successive Michael and amino-Michael substitution reactions of 2,3-dichloro-1,4-naphthoquinone has been used to rapidly construct the ABCD ring system of the pyrroloacridine natural product alpkinidine.

Chemical investigation of the Mediterranean ascidian A. conicum resulted in the isolation of two new meroterpenes, the conithiaquinones A (1) and B (2), in addition to two previously reported chromenols (3 and 4) and conicaquinones (5 and 6). The structures of conithiaquinones A and B were determined by interpretation of spectroscopic data, and regiochemical and stereochemical assignments were achieved with the aid of computational methods, including the recently developed DP4 NMR spectral prediction method. Both conithiaquinones A and B showed significant effects on the growth and viability of cells, with 1 showing interesting cytotoxicity against human breast cancer cells.

Two meroterpenes, conithiaquinones A (1) and B (2), were isolated from the ascidian A. conicum, and their stereochemical structures were determined with the aid of computational methods, including the recently developed DP4 NMR spectral prediction method. Both conithiaquinones showed significant effects on cell viability, with 1 showing an interesting cytotoxicity against human breast cancer cells.

The crystal structures of simple triphenyl(pentafluorobenzyl)phosphonium salts provide crucial data on the influence of anion size on the molecular structure of bis(pentafluorobenzyl)phosphonium cations containing two adjacent electron-deficient moieties. Whereas the bromide anions interact by anion-π interaction in a 1:1 mode with the pentafluorobenzene unit Z-configured, the bulkier anions iodide, tetrafluoroborate, and hexafluorophosphate result in a 1:2 tweezer-like anti-configuration in which one anion interacts simultaneously with two pentafluorobenzene units. When spatial separation of the two electron-deficient rings match the size of the anion, anion-π interactions induce a conformational change from the anti-form observed for the smaller anion to the tweezer-like syn-form.

The solid-state structures of a series of bis(pentafluorobenzyl)phosphonium salts reveal the crucial relevance of anion size in anion-π interactions, leading to conformational control.

The binding behaviour of (thio)urea- and amide-functionalized quinoline-based anion receptors towards halide anions was investigated in detail in CDCl₃ and [D₆]DMSO solutions by using ¹H and ¹⁹F NMR spectroscopic methods. The electronic, solvent, and fluoro-substitution effects were studied. The (thio)urea- and amide-functionalized quinoline-based anion receptors showed medium to strong anion affinity and good selectivity in solution. Single crystals of key compounds were obtained and studied by X-ray diffraction spectroscopy.

We have investigated in detail the binding behaviour of (thio)urea- and amide-functionalized quinoline-based anion receptors towards halide anions in CDCl₃ and [D₆]DMSO solutions by using ¹H and ¹⁹F NMR spectroscopic methods. The electronic effects, solvent effects and fluoro-substitution effects were studied. Single crystals were obtained and analysed by X-ray diffraction spectroscopy.

A new class of twin-chain hydroxyalkylthiols (mercaptoalkanols) is described that features a nearly constant cross section and the potential for modification at one or both termini. These compounds are regioselectively available through Pd-mediated couplings of benzene diiododitriflate, and their syntheses include an example of a previously unreported coupling reaction to generate an ortho-substituted arene bis(acetic acid). In an electrochemical sensor system, the self-assembled monolayers (SAMs) that were prepared from the new amphiphiles demonstrate an improved stability in comparison to the monolayers prepared from analogous single-chain thiols.

A new class of twin-chain hydroxyalkylthiols (mercaptoalkanols) is described that features a constant cross section and the potential for modification at one or both termini. Under conditions for surface electrochemical sensing, these derived monolayers displayed greater stability than the self-assembled monolayers (SAMs) that were prepared from analogous single-chain amphiphiles.

The first total synthesis of eudistomin Y₇ (7) and total syntheses of eudistomins Y₁–Y₆ (1–6) are described. An efficient room-temperature conversion of 1-benzyl-3,4-dihydro-β-carbolines (11) into 1-benzoyl-β-carbolines (14) by a one-pot process of tandem benzylic oxidation and aromatization as the key step of these total syntheses was also studied in detail.

The first total synthesis of eudistomin Y₇ (7) and total syntheses of eudistomins Y₁–Y₆ (1–6) are described. An efficient room-temperature conversion of 1-benzyl-3,4-dihydro-β-carbolines (11) into 1-benzoyl-β-carbolines (14) by a one-pot process of tandem benzylic oxidation and aromatization as the key step of these total syntheses was also studied in detail.

We describe straightforward routes either to α-bromo-α-fluoro-β-hydroxy amides or to (Z)-α-fluoroacrylamides starting from aldehydes, ketones or imine and 2,2-dibromo-2-fluoroacetamides. Depending on the nature of the amide, these diethylzinc-mediated additions to aldehydes, ketones or imine afford selective access either to bromofluorohydrins or to (Z)-α-fluoroacrylamides. The corresponding products were obtained in moderate to very good yields and the configurations of both products were confirmed by X-ray analyses.

Reactions between aldehydes, ketones or imines and 2,2-dibromo-2-fluoroacetamides, a new class of fluorinated reagent, allow straightforward selective access to α-bromo-α-fluoro-β-hydroxy amides and/or (Z)-α-fluoroacrylamides with moderate to excellent yields.

Intramolecular aza-Wittig ring closures were applied to synthesize thiazolines, oxazolines, and imidazolines from β-azido thioester, ester, and amide precursors. The cyclization precursors were obtained from amino acid derivatives. Optimized conditions for diazo transfer with a fast rate and racemization suppression, (thio)esterification, and amide coupling reactions are described. The ring closure reaction can be executed with PPh₃ under neutral conditions and was found to be highly chemoselective for five-membered rings. If amide groups were activated with tosyl groups, smooth intramolecular ring closure of iminophosphoranes furnished enantiopure imidazoline products with position-specific tosyl protection. This aza-Wittig-based azoline synthesis was then extended to double azoline ring closures to furnish catenated azoline building blocks common to peptide natural product building blocks and their analogues.

Intramolecular aza-Wittig ring closures have been developed to synthesize thiazolines, oxazolines, and imidazolines from β-azido thioester, ester, and amide precursors. Optimized conditions for diazo transfer with ZnSO₄ as catalyst are described. General aza-Wittig-based azoline synthesis for single and double azoline ring closures have been studied in depth and optimized.

Functionalized acylfuranones have been prepared in a one-step procedure by thermal fragmentation of the corresponding dioxinones in the presence of hydroxy ketones in basic conditions. Multicomponent reactions also occur on addition of an aldehyde as a third reaction partner resulting in an expeditious access to cadiolide B and its analogues.

A new method for the synthesis of acylfuranones is described based on the fragmentation of dioxinones to acylketenes followed by trapping with hydroxy ketones. Addition of an aldehyde as a third reaction partner leads to a supplementary aldolization/crotonization sequence resulting in an expeditious synthesis of cadiolide B and its analogues.

Fischer indole cyclization has recently been described as an efficient approach to the synthesis of azaindoles bearing electron-donating groups. We now show that this cascade reaction can be very efficient for the formation of a wider range of 4- and 6-azaindoles by using microwave irradiation.

Fischer indole cyclization starting from aminopyridines is a very efficient cascade sequence leading to 4- and 6-azaindoles. The scope of the substituents on the pyridine ring was extended to include halogens and to weakly electron-donating substituents by using microwave irradiation.

An efficient one-pot method for the regioselective bromination of allylic alcohol derivatives (two-step reaction sequence) followed by Sonogashira, Negishi, or Suzuki–Miyaura coupling reactions in the same reaction vessel (three-step reaction sequence) has been developed. The key reaction in these one-pot systems is the regioselective DBU-promoted trans HBr elimination of vicinal dibromides bearing an adjacent O-functional group.

Di- or trisubstituted olefins were synthesized in high yields with excellent regio- and cis–trans selectivities in one-pot reactions, including a regioselective DBU-promoted trans HBr elimination. This one-pot methodology could become a straightforward transformation of “straight” alkenes into “Y-shaped” alkenes.

Tris(2,3,5,6-tetrathiaaryl)methyl cations, which were generated from the corresponding triarylmethanols in the presence of strong acids, underwent reaction with nucleophiles to give trityl radicals, as the product of a one-electron reduction of the carbocation. Depending on the nature of the nucleophile, the only byproducts were either diamagnetic quinone methides or asymmetrical monosubstituted trityl radicals. Herein, we report a protocol for the large-scale synthesis of the Finland trityl, which has the advantage of high overall yield and reproducibility.

Tris(2,3,5,6-tetrathiaaryl)methyl cations, which were generated from the corresponding triarylmethanols and strong acids, underwent reaction with nucleophiles to give trityl radicals. Depending on the nucleophile, the only byproducts were diamagnetic quinone methides or asymmetrical monosubstituted trityl radicals. A protocol for the large-scale synthesis of the Finland trityl is reported.

Hydroalumination of cyanamides 1 with di(isobutyl)aluminium hydride affords intermediate compounds 3, which have dimeric structures in the solid state with four-membered Al₂N₂ heterocycles and exocyclic N=C double bonds. The reactions of 3 with acyl chlorides yield N′,N′-disubstituted N-acylformamidines 5, whereas reaction with sulfonyl chlorides give the corresponding N-sulfonylformamidines 7. In contrast, carbodiimides 8 react with dialkylaluminium hydrides R₂AlH (R = tBu, iBu) to give compounds 9 in which one C=N bond of the carbodiimide is reduced to form an amidinate ligand and a second molecule of the hydride is coordinated through an Al–N and an Al–H–Al bond. Treatment of 9 with acyl chlorides yields N,N′-disubstituted N-acylformamidines 10, whereas reaction with sulfonyl chlorides gives the corresponding N-sulfonylformamidines 11.

In a simple one-pot procedure cyanamides are converted into N′,N′-disubstituted N-acyl- or N-sulfonylformamidines by hydroalumination and subsequent treatment with acyl- or sulfonyl chlorides. Carbodiimides react similarly, forming N,N′-disubstituted N-acyl- and N-sulfonylformamidines. The intermediate aluminium compounds and several products were characterised, including by X-ray crystallography.

The nucleophilicity parameters N and s_N, as defined by the linear free-energy equation log k(20 °C) = s_N(N + E), of the 2-imidazolines 1a–d and the related N-heterocyclic compounds 2–5 have been determined by studying the rates of their reactions with differently substituted benzhydrylium ions in dichloromethane at 20 °C by stopped-flow or laser flash photolysis techniques. It is demonstrated that the N and s_N parameters thus obtained can be used to reliably predict the rate constants for their reactions with Michael acceptors of known electrophilicity E. A comparison of the nucleophilicity parameters of the imidazoline derivatives 1 with other commonly used nucleophilic organocatalysts shows that they are 10 to 10³ times less nucleophilic than PPh₃, 1,8-diazabicyclo[5.4.0]undec-7-ene, or 4-(dimethylamino)pyridine. The structure–reactivity relationships of these heterocycles are discussed.

Rate and equilibrium constants for the reactions of 2-imidazolines and related N-heterocyclic compounds with diarylcarbenium ions have been measured in CH₂Cl₂ at 20 °C. These data were employed to determine their nucleophilicities and Lewis basicities, which were compared with other nucleophilic organocatalysts.

A synthetic method was developed for the preparation of heteroaryl and diheteroaryl ketones from aldehydes and organoboronic acids through a palladium-catalyzed 1,2-addition and oxidation that uses an aryl iodide as the oxidant. This one-pot process shows high tolerance for a broad range of heterocyclic substrates by using 1.0–3.0 mol-% of the catalyst that is formed from allylpalladium chloride dimer and a thioether-imidazolinium chloride. In addition to fine-tuning the catalytic system, the use of a sterically hindered aryl iodide that has a substituent at the ortho position, such as 2-iodotoluene, is important to obtain the desired ketones with heterocyclic moieties in good to excellent yields.

The one-pot synthesis of heteroaryl and diheteroaryl ketones was achieved by a palladium-catalyzed 1,2-addition and oxidation. This catalytic process with 1.0–3.0 mol-% catalyst loading tolerates a broad range of heterocyclic substrates to give ketones with heterocyclic moieties in good to excellent yields.

A facile iodine/water-mediated oxidation of the triple bond of o-alkynylaroyl compounds to furnish tricarbonyl compounds is reported. The reaction proceeds through the formation of isochromenol intermediates by the assistance of the neighbouring aroyl group. The product tricarbonyl compounds are versatile synthetic precursors that, upon treatment with mono- and diamines, hydrazines and amino alcohols, afford various heterocyclic scaffolds such as isoindolinones, phthalazines, benzimidazoisoquinolinones, quinoxalines and benzimidazole-quinoxaline hybrid compounds. Mechanistic aspects of the formation of the above heterocycles are discussed. Finally, a short synthetic route to the isoindolinone natural product, aristolactam BII is reported.

Tricarbonyl compounds obtained from the oxidation of o-alkynylaroyl compounds using an iodine/water system act as useful precursors for the synthesis of a diverse range of heterocycles, including a natural product.

A short and efficient total synthesis of the alkaloid isosolenopsin and its enantiomer has been achieved. The key step was a ω-transaminase-catalysed regioselective monoamination of the diketone pentadecane-2,6-dione, which was obtained in a single step through the application of a Grignard reaction. Initial low conversions in the biotransformation could be overcome by optimisation of the reaction conditions employing suitable cosolvents. In the presence of 20 vol.-% N,N-dimethylformamide (DMF) or n-heptane the best results were obtained by employing two enantiocomplementary ω-transaminases originating from Arthrobacter at 30–40 °C; under these conditions, conversions of more than 99 % and perfect stereocontrol (ee > 99 %) were achieved. Diastereoselective chemical reduction (H₂/Pd/C) of the biocatalytic product gave the target compound. The linear three-step synthesis provided the natural product isosolenopsin in diastereomerically pure form (ee > 99 %, dr = 99:1) with an overall yield of 64 %.

The alkaloid isosolenopsin was prepared in three steps. The optimised biocatalytic step used DMF as cosolvent and gave excellent conversion (up to > 99 %) and perfect regio- and stereoselectivity. After chemical reduction, isosolenopsin was obtained in diastereomerically pure form with more than 99 % ee.