Total Synthesis of (−)‐Morphine

We have developed an efficient total synthesis of (?)‐morphine in 5 % overall yield with the longest linear sequence consisting of 17 steps from 2‐cyclohexen‐1‐one. The cyclohexenol unit was prepared by means of an enzymatic resolution and a Suzuki–Miyaura coupling as key steps. Construction of the morphinan core features an intramolecular aldol reaction and an intramolecular 1,6‐addition. Furthermore, mild deprotection conditions to remove the 2,4‐dinitrobenzenesulfonyl (DNs) group enabled the facile construction of the morphinan skeleton. We have also established an efficient synthetic route to a cyclohexenol unit containing an N‐methyl‐DNs‐amide moiety.     

The Crystal Structure of RosB: Insights into the Reaction Mechanism of the First Member of a Family of Flavodoxin‐like Enzymes

8‐demethyl‐8‐aminoriboflavin‐5′‐phosphate (AFP) synthase (RosB) catalyzes the key reaction of roseoflavin biosynthesis by forming AFP from riboflavin‐5′‐phosphate (RP) and glutamate via the intermediates 8‐demethyl‐8‐formylriboflavin‐5′‐phosphate (OHC‐RP) and 8‐demethyl‐8‐carboxylriboflavin‐5′‐phosphate (HO₂C‐RP). To understand this reaction in which a methyl substituent of an aromatic ring is replaced by an amine we structurally characterized RosB in complex with OHC‐RP (2.0 Å) and AFP (1.7 Å). RosB is composed of four flavodoxin‐like subunits which have been upgraded with specific extensions and a unique C‐terminal arm. It appears that RosB has evolved from an electron‐ or hydride‐transferring flavoprotein to a sophisticated multi‐step enzyme which uses RP as a substrate (and not as a cofactor). Structure‐based active site analysis was complemented by mutational and isotope‐based mass‐spectrometric data to propose an enzymatic mechanism on an atomic basis.     

Bis(1,3‐dithiol‐2‐ylidene)‐Substituted Subtriazachlorin: A Subphthalocyanine Analogue with Redox Properties

Bis(1,3‐dithiol‐2‐ylidene)‐substituted subtriazachlorin was formed because of an unusual reaction of a 1,3‐dithiole‐2‐one‐fused subphthalocyanine in a triethylphosphite‐mediated tetrathiafulvalene synthesis. In this novel molecule, the bis(1,3‐dithiol‐2‐ylidene)ethane moiety and subtriazachlorin structure are fused, resulting in an electron‐donating ability and broad absorption in the near‐infrared region.     

Selective Transformations of a Diprotected 2‐Oxobutanedial

The reactivity of 1,1‐diethoxy‐3‐(1,3‐dithian‐2‐yl)propan‐2‐one, a diacetal of oxobutanedial, and some of its derivatives toward selected reagents has been studied. As expected, hydride and Grignard‐type additions take place at the oxo moiety only and give the corresponding alcohols in good‐to‐excellent yields. Standard reductive amination occurs at the oxo moiety as well, but the reaction was in most cases not selective and furnished the expected amine mixed with 3‐(1,3‐dithian‐2‐yl)‐1,1‐diethoxypropan‐2‐ol. The conversion of the diethyl acetal moiety to an aldehyde group is generally an efficient transformation, but some aldehydes are unstable, making the deprotection useless. If the acetal contains a tertiary alcohol or a benzyloxy moiety, however, stable products are formed in good yields. Attempts to convert the 1,3‐dithiane substituent into an aldehyde group without concomitant decomposition of the product were totally unsuccessful. The chemical potential of this moiety, therefore, has to be utilized at an earlier stage and under different conditions.     

Real‐time lock‐in energy loss imaging with a novel high‐speed image processing CCD video camera

We have developed a high‐speed image processing CCD video camera for real‐time energy‐loss imaging using a conventional electron microscope with an energy‐loss imaging facility. As an initial demonstration of real‐time lock‐in energy‐loss imaging, a background‐subtracted energy‐loss image was observed by attaching the high‐speed image processing CCD video camera to an analytical electron microscope equipped with a floating‐type energy‐loss imaging analyser. Copyright © 2003 John Wiley & Sons, Ltd.     

Theoretical Analysis of the Detailed Mechanism of Native Chemical Ligation Reactions

The method of native chemical ligation between an unprotected peptide α‐thioester and an N‐terminal cysteine–peptide to give a native peptide in aqueous solution is one of the most effective peptide ligation methods. In this work, a systematic theoretical study was carried out to fully understand the detailed mechanism of ligation. It was found that for the conventional native chemical ligation reaction between a peptide thioalkyl ester and a cysteine in combination with an added aryl thiol as catalyst, both the thiol‐thioester exchange step and the transthioesterification step proceed by an anionic concerted S_N2 displacement mechanism, whereas the intramolecular rearrangement proceeds by an addition–elimination mechanism, and the rate‐limiting step is the thiol‐thioester exchange step. The theoretical method was then extended to study the detailed mechanism of the auxiliary‐mediated peptide ligation between a peptide thiophenyl ester and an N‐2‐mercaptobenzyl peptide in which both the thiol‐thioester exchange step and intramolecular acyl‐transfer step proceed by a concerted S_N2‐type displacement mechanism. The energy barrier of the thiol‐thioester exchange step depends on the side‐chain steric hindrance of the C‐terminal amino acid, whereas that of the acyl‐transfer step depends on the side‐chain steric hindrance of the N‐terminal amino acid.     

Facile Synthesis of Chiral Spirooxindole‐Based Isotetronic Acids and 5‐1H‐Pyrrol‐2‐ones through Cascade Reactions with Bifunctional Organocatalysts

Unprecedented organocatalyzed asymmetric cascade reactions have been developed for the facile synthesis of chiral spirooxindole‐based isotetronic acids and 5‐1H‐pyrrol‐2‐ones.The asymmetric 1,2‐addition reactions of α‐ketoesters to isatins and imines by using an acid–base bifunctional 6′‐OH cinchona alkaloid catalyst, followed by cyclization and enolization of the resulting adducts, gave chiral spiroisotetronic acids and 5‐1H‐pyrrol‐2‐ones, respectively, in excellent optical purities (up to 98 % ee). FT‐IR analysis supported the existence of hydrogen‐bonding interaction between the 6′‐OH group of the cinchona catalyst and an isatin carbonyl group, an interaction that might be crucial for catalyst activity and stereocontrol.     

Stimuli‐Responsive Dual‐Color Photon Upconversion: A Singlet‐to‐Triplet Absorption Sensitizer in a Soft Luminescent Cyclophane

Reversible emission color switching of triplet–triplet annihilation‐based photon upconversion (TTA‐UC) is achieved by employing an Os complex sensitizer with singlet‐to‐triplet (S‐T) absorption and an asymmetric luminescent cyclophane with switchable emission characteristics. The cyclophane contains the 9,10‐bis(phenylethynyl)anthracene unit as an emitter and can assemble into two different structures, a stable crystalline phase and a metastable supercooled nematic phase. The two structures exhibit green and yellow fluorescence, respectively, and can be accessed by distinct heating/cooling sequences. The hybridization of the cyclophane with the Os complex allows near‐infrared‐to‐visible TTA‐UC. The large anti‐Stokes shift is possible by the direct S‐T excitation, which dispenses with the use of a conventional sequence of singlet–singlet absorption and intersystem crossing. The TTA‐UC emission color is successfully switched between green and yellow by thermal stimulation.     

Chemical Synthesis of Human Insulin‐Like Peptide‐6

Human insulin‐like peptide‐6 (INSL‐6) belongs to the insulin superfamily and shares the distinctive disulfide bond configuration of human insulin. In this report we present the first chemical synthesis of INSL‐6 utilizing fluorenylmethyloxycarbonyl‐based (Fmoc) solid‐phase peptide chemistry and regioselective disulfide bond construction protocols. Due to the presence of an oxidation‐sensitive tryptophan residue, two new orthogonal synthetic methodologies were developed. The first method involved the identification of an additive to suppress the oxidation of tryptophan during iodine‐mediated S‐acetamidomethyl (Acm) deprotection and the second utilized iodine‐free, sulfoxide‐directed disulfide bond formation. The methodologies presented here offer an efficient synthetic route to INSL‐6 and will further improve synthetic access to other multiple‐disulfide‐containing peptides with oxidation‐sensitive residues.     

One‐Pot Cannizzaro Cascade Synthesis of ortho‐Fused Cycloocta‐2,5‐dien‐1‐ones from 2‐Bromo(hetero)aryl Aldehydes

An intramolecular Cannizzaro‐type hydride transfer to an in situ prepared allene enables the synthesis of ortho‐fused 4‐substituted cycloocta‐2,5‐dien‐1‐ones with unprecedented technical ease for an eight‐ring carboannulation. Various derivatives could be obtained from commercially available (hetero)aryl aldehydes, trimethylsilylacetylene, and simple propargyl chlorides in good yields.     

Total Synthesis of the Antibiotic Kendomycin: A Macrocyclization Using the Tsuji–Trost Etherification

A highly stereocontrolled, convergent total synthesis of kendomycin [(?)‐TAN2162], an ansa‐macrocyclic antibiotic, is reported. The key of the strategy is an unprecedented Tsuji–Trost macrocyclic etherification, followed by a transannular Claisen rearrangement to construct the 18‐membered carbocyclic framework. The oxa‐six‐ and five‐membered rings were also stereoselectively constructed respectively by a cascade oxidative cyclization at an unfunctionalized benzylic position and using a one‐pot epoxidation/5‐exo‐tet epoxide opening.     

Synthesis of 1‐Arylethyl‐2‐arylethylamino‐5‐trifluoroacetyl‐1,2,3,4‐tetrahydropyridines and Related Compounds with Potential Cell Efflux Pump Inhibition

This study reports a simple, fast, and efficient method for the synthesis of a new series of 1‐arylethyl‐2‐arylethylamino‐5‐trifluoroacetyl‐1,2,3,4‐tetrahydropyridines and related compounds from the reaction of 2‐alkoxy‐5‐trifluoroacetyl‐3,4‐dihydro‐2H‐pyrans with 2‐arylethanamines and related 2‐ethanamines. The desired tetrahydropyridines were obtained in excellent yields (90–98%), through a reaction that can be described as an AAB′ three‐component reaction protocol following an ANRORC‐type mechanism.     

Beyond the Corey–Chaykovsky Reaction: Synthesis of Unusual Cyclopropanoids via Desymmetrization and Thereof

Desymmetrization‐based protocols for the synthesis of highly functionalized indeno‐spirocyclopropanes and cyclopropa‐fused indanes have been established through unexpected reactions triggered by the Corey–Chaykovsky reagent. These structures were further elaborated in one step to privileged scaffolds such as fluorenones, indenones, and naphthaphenones. For instance, an acid‐catalyzed transformation of indeno‐spirocyclopropanes provided fluorenones via a homo‐Nazarov‐type cyclization, and naphthaphenones were obtained via an acid‐catalyzed cyclopropane ring‐opening/retro‐Michael sequence.     

Dihydropyran as a Template for Lactone Synthesis

3,4‐Dihydro‐2H‐pyran (DHP) was efficiently transformed into 4‐thiophenyl‐3,4‐dihydro‐2H‐pyran. This intermediate was converted to the corresponding 1,3‐O,S‐allylic carbanion with t‐butyllithium and selectively alkylated at the carbon α to the sulfur with alkyl halides, an epoxide, and an aldehyde. An one‐pot oxidative elimination of the sulfur fragment using vanadium pentoxide generates the desired β‐substituted α,β‐unsaturated δ‐valero lactone.     

Designing an “A‐Ring‐with‐Branches” Polymer Topology by Electrostatic Self‐Assembly and Covalent Fixation with Interiorly Functionalized Telechelics Having Cyclic Ammonium Groups

A novel and unusual polymer topology, i.e. a‐ring‐with‐two‐branches, has been constructed efficiently by making use of an interiorly functionalized poly(tetrahydrofuran) (poly(THF)) having two pyrrolidinium groups. The dicarboxylate counterion, i. e. terephthalate, was then introduced by an ion‐exchange reaction of the interiorly located pyrrolidinium group. Subsequent heat treatment under appropriate dilution caused an efficient polymer cyclization to produce an a‐ring‐with‐two‐branches polymer topology in high yield through the selective and quantitative ring‐opening of the pyrrolidinium groups by the dicarboxylate counterion.     

New Squaraine‐based two‐component initiation systems for UV‐blue light induced radical polymerization: Kinetic and time‐resolved laser spectroscopy studies

In this article, the ability of two‐component photoinitiator systems for efficient polymerization of 2‐ethyl‐2‐(hydroxymethyl)?1,3‐propanediol triacrylate was presented. The photophysics and photochemistry of squaraine dyes in the presence of an electron donor as well as an electron acceptor was investigated, and it was found that the photosensitizer in an excited state might act as an electron acceptor or an electron donor. The excited states of squaraines may be quenched by tetramethylammonium n‐butyltriphenylborate ( B2 ), diphenyliodonium chloride ( I1 ), and N‐methoxy‐4‐phenylpyridinium tetrafluoroborate ( NO ). © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55 , 471–484     

Unprecedented Role of Hydronaphthoquinone Tautomers in Biosynthesis

Quinones and hydroquinones are among the most common cellular cofactors, redox mediators, and natural products. Here, we report on the reduction of 2‐hydroxynaphthoquinones to the stable 1,4‐diketo tautomeric form of hydronaphthoquinones and their further reduction by fungal tetrahydroxynaphthalene reductase. The very high diastereomeric and enantiomeric excess, together with the high yield of cis‐3,4‐dihydroxy‐1‐tetralone, exclude an intermediary hydronaphthoquinone. Labeling experiments with NADPH and NADPD corroborated the formation of an unexpected 1,4‐diketo tautomeric form of 2‐hydroxyhydronaphthoquinone as a stable intermediate. Similar 1,4‐diketo tautomers of hydronaphthoquinones were established as products of the NADPH‐dependent enzymatic reduction of other 1,4‐naphthoquinones, and as substrates for different members of the superfamily of short‐chain dehydrogenases. We propose an essential role of hydroquinone diketo tautomers in biosynthesis and detoxification processes.     

Fe(OTf)3‐Catalyzed α‐Benzylation of Aryl Methyl Ketones with Electrophilic Secondary and Aryl Alcohols

Acid‐catalyzed Friedel–Crafts alkylation of 1,3‐dicarbonyl compounds with electrophilic alcohols, is known to be an effective C? C bond forming reaction. However, until now, this reaction has not been amenable for α‐alkylation of aryl methyl ketones because of the notoriously low nucleophilicities of these compounds. Therefore, α‐alkylation of aryl methyl ketone relies on precious metal catalysts and also, the use of primary alcohols is mandatory. In this study, we found that a system composed of a Fe(OTf)₃ catalyst and chlorobenzene solvent is sufficient to promote the title Friedel–Crafts reaction by using benzhydrols as electrophiles. 3,4‐Dihydro‐9‐(2‐hydroxy‐4,4‐dimethyl‐6‐oxo‐1‐cyclohexen‐1‐yl)‐3,3‐dimethyl‐xanthen‐1(2 H)‐one was also applicable as an electrophile in this type of benzylation reaction. On the basis of this result, a three‐component reaction of salicylaldehyde, dimedone, and aryl methyl ketone was also developed, and this provided an efficient way for the synthesis of densely substituted 4H‐chromene derivatives.     

Statistical Conjugated Polymers Comprising Optoelectronically Distinct Units

Poly(3‐heptylselenophene)‐stat‐poly(3‐hexylthiophene) is synthesized and characterized in terms of its crystallinity and performance in an organic photovoltaic (OPV) cell. Despite the random distribution of units along the polymer main chain, the material is semi‐crystalline, as demonstrated by differential scanning calorimetry and wide‐angle X‐ray diffraction. Thin‐film absorption suggests an increased compatibility than seen with 3‐hexylselenophene monomer. Optoelectronic properties are an average of the two homopolymers, and OPV performance is enhanced by a broadened absorption profile and a favorable morphology.     

Novel Route to (+)‐Pinitol Intermediate via a Strategy Derived from Diazotization of O‐Isopropylidene‐Protected 4‐Amino‐2‐Cyclohexen‐1‐ol

A concise preparation of the enantiopure 1,2‐(isopropylidenedioxy)‐3,4‐epoxy‐5‐cyclohexene 2b , which is an important building block for (+)‐pinitol synthesis, evolved by combining the asymmetric cycloaddition of isopropylidenedioxy)cyclohexadiene to chiral chloronitroso with an internal substitution of an amino alcohol to create vinyl epoxide.