On the basis of an easy access to 2,2′:6′,2″-terpyridine derivatives bearing 6- and 6″-methyl groups, the functionalization of these substituents was investigated. The direct oxidation or bromination of the methyl groups was not feasible on larger scale; however, a two-step process employing oxidation to the pyridine N-oxides followed by acetic anhydride promoted rearrangement (Boekelheide reaction) furnished the corresponding terpyridine derivatives with 6- and 6″-acetoxymethyl groups in reasonable overall yields. These are excellent precursors for the synthesis of tetra- and pentadentate ligands, as demonstrated by several examples. This approach allowed access to a library of new functionalized 2,2′:6′,2″-terpyridine derivatives.

Following up on our previous model studies on the synthesis of simple bisbenzannulated [5,6]-spiroketals we here report the preparation of new examples of this entity with a variation in their substitution pattern. The regioselective introduction of functional groups in the C-3 or C-3′ positions (rubromycin numbering) may either take place prior to the spiroketalization by α-functionalizations of the ketone moiety of the precursor or in a subsequent step by the nucleophilic substitution of the benzylic hydroxy group of the previously described C-3-hydroxylated spiroketal. By applying these methods we could synthesize new methyl-substituted, hydroxylated, halogenated and amino-substituted bisbenzannulated [5,6]-spiroketals in good overall yields.

A detailed study of the nucleophilic aromatic substitution reaction of meso-pentafluorophenyl-substituted tetrapyrrole systems with different alcohols is presented. The systematic investigation of various alcohols and bases in two different solvents led to optimized reaction conditions, allowing the selective substitution of the p-fluorine atoms of meso-pentafluorophenyl-substituted porphyrins, their zinc complexes, and a meso-tris(pentafluorophenyl)corrole with alcohols and a simple base in high yields. When applied to A₃B porphyrins in combination with suitable protecting groups, functionalized, polar A₃B porphyrins can be prepared in a simple two-step one-pot procedure. By using the nucleophilic aromatic substitution reaction, a dimeric porphyrin system was synthesized. In addition, the copper(I)-catalyzed 1,3-dipolar cycloaddition of properly functionalized meso-pentafluorophenyl-substituted porphyrins led to the corresponding porphyrin dimer with a 1,2,3-triazole linker. The method described herein allows a simple and fast approach towards multifunctionalized porphyrinoids based on meso-pentafluorophenyl-substituted tetrapyrroles.

The copper(I)-catalyzed 1,3-dipolar cycloaddition of 4-azido(tetrafluorophenyl)boron-dipyrrin (azido-BODIPY) with diverse terminal alkynes, varying from simple alkyl-substituted derivatives to alkynes with functional groups and carbohydrates, was successfully employed to obtain meso-functionalized BODIPY derivatives through the 1,2,3-triazole linkage. The scope of this reaction was extended to the preparation of di- and trivalent BODIPY systems through the use of appropriate alkynyl linkers. Moreover, the synthesis of hydroxyl- and pentafluorothio-(SF₅)-substituted, 1,2,3-triazole-linked array systems consisting of porphyrins and corroles as the central scaffold, in combination with a BODIPY, was investigated. These covalently connected tetrapyrrole-BODIPY arrays exemplify a versatile approach to the construction of multichromophore systems: the combination of 1,3-dipolar cycloaddition and nucleophilic substitution on pentafluorophenyl-substituted porphyrinoids. The systems designed herein could serve in various light-harvesting applications and electron-transfer studies.

A modular approach to aryl C-glycosides and their multivalent analogues is presented. Sonogashira coupling reactions connected the key compounds, enantiopure bicyclic 1,2-oxazine derivatives bearing p-bromophenyl substituents, with alkynes. Subsequent hydrogenolyses or a combination of hydrogenolysis and samarium diiodide mediated reductions converted the coupling products into new unnatural amino carbohydrate mimetics with a D-talose configuration. By Glaser coupling reactions we obtained products with a 1,3-diyne linker and divalent compounds derived therefrom. Through Sonogashira reactions of compound 8 with several iodobenzene derivatives, di-, tri-, and tetravalent compounds were prepared in high yields. The subsequent reductive processes converted the 1,2-oxazine moieties into the corresponding aminopyrans. Severe purification problems were solved in most cases by following the appropriate strategies as an apt sequence of steps or by acetylation of the intermediates.

Samarium diiodide mediated cyclizations of N-acylated indole derivatives bearing sulfinyl imine moieties afforded polycyclic tertiary carbinamines with moderate to excellent diastereoselectivities. Lithium bromide and water turned out to be the best additives to achieve these transformations in good yields. Using enantiopure sulfinyl imines the outcome strongly depends on the reactivity of the indole moiety. Whereas with unactivated indole derivatives desulfinylation and formation of racemic products was observed, indoles bearing electron-withdrawing substituents at C-3 afforded the polycyclic products with intact N-sulfinyl groups and with excellent diastereoselectivity, finally allowing the preparation of enantiopure tertiary carbinamines. The mechanisms of these processes are discussed.

Invited for the cover of this issue is the group of Hans-Ulrich Reissig at the Freie Universität Berlin. The image depicts several aspects of strychnine’s provenience and a new approach towards its synthesis. Read the full text of the article at 10.1002/chem.201500094.

New conditions for dearomatizing samarium-ketyl (hetero)arene cyclizations are reported. In many examples of these samarium diiodide-mediated reactions, lithium bromide and water can be used as additives instead of the carcinogenic and mutagenic hexamethylphosphoramide (HMPA). The best results were obtained for the cyclizations of N-acylated indole derivatives delivering the expected indolines in good yields and excellent diastereoselectivities. A new type of cyclization delivering indolyl-substituted allene derivatives is also described. The scope and limitations of the lithium bromide/water system are discussed.

This comprehensive report accounts the development of a highly diastereoselective samarium diiodide-induced cascade reaction of substituted indolyl ketones. The complexity-generating transformation with SmI₂ allows the diastereoselective generation of three stereogenic centers including one quaternary center in one step. The obtained tetra- or pentacyclic dihydroindole derivatives are structural motifs of many monoterpene indole alkaloids, and their subsequent transformations gave way to one of the shortest approaches towards strychnine (14 % overall yield in ten steps, or 10 % overall yield in eight steps). During the course of this report we discuss the influence of substituents on the cyclization step, plausible mechanistic scenarios for the SmI₂-induced cascade reaction, diastereoselective reductive amination, and regioselective dehydratization protocols towards the pentacyclic core structure of strychnos alkaloids.

Samariumdiiodid-vermittelte Cyclisierungen von N-acylierten Indolderivaten mit Sulfinyliminmotiv lieferten polycyclische tertiäre Carbinamine in mäßigen bis exzellenten Diastereoselektivitäten. Lithiumbromid und Wasser erwiesen sich als die geeignetsten Additive, um gute Ausbeuten bei dieser Transformation zu erzielen. Bei Einsatz enantiomerenreiner Sulfinylimine hing das Resultat maßgeblich von der Reaktivität der Indolyleinheit ab. Nicht aktivierte Indolderivate erfuhren eine Desulfinylierung und ergaben racemische Produkte, wogegen die Verwendung von Indolen mit elektronenanziehenden Substituenten an C-3 polycyclische Produkte mit intakter N-Sulfinylgruppe mit sehr guten Diastereoselektivitäten lieferte, was letztlich die Herstellung enantiomerenreiner tertiärer Carbinamine ermöglichte. Die Mechanismen dieser Prozesse werden diskutiert.

A series of enantiopure poly(hydroxy)aminooxepanes was converted into the corresponding azidooxepanes by a safe and efficient copper(II)-catalyzed diazo transfer reaction employing nonafluorobutanesulfonyl azide as nitrogen donor. These azidooxepanes underwent smooth copper(I)-catalyzed [3+2] cycloadditions with alkynes (click reaction) to provide a series of simple triazoles. With dialkynes and a trialkyne, bis- and tristriazoles containing oxepane substructures were prepared. Due to the polyhydroxylated end groups, these compounds are regarded as carbohydrate mimetics with potential biological activities, for example, as selectin inhibitors. In addition, unsymmetrical systems and macrocyclic compounds were prepared, again by employing [3+2] cycloadditions as key steps.

Two different lithiated alkoxyallenes and the enantiopure L-erythrose-derived cyclic nitrone (+)-3 were used as precursors for the preparation of novel bicyclic 2H-1,2-oxazine derivatives, which were formed as single diastereomers. A highly stereoselective hydroboration/oxidation sequence provided key substrates that were suitable for the synthesis of a series of polyhydroxylated bicyclic N-heterocycles, including unique 5-oxaindolizidines such as 8 and 12. Depending on the protecting groups installed, a straightforward ring-opening/recyclization protocol allowed the preparation of the corresponding pyrrolizidines bearing two, three or four free hydroxy groups. By inversion of the order of reaction steps, the synthesis of novel isomeric azabicyclo[3.2.0]heptane derivatives that are the lower homologues of pyrrolizidines and indolizidines were achieved. The prepared novel polyhydroxylated compounds were examined for their property as glycosidase inhibitors, but none of the compounds showed noteworthy activity.

Flexible and straightforward syntheses of a series of D_3h- or C_3h-symmetrical star-shaped compounds with pyridine end groups are reported. In all cases, the acid-mediated cyclocondensations of the corresponding aryl methyl ketone provided the central benzene ring. For the preceding preparation of the functionalized compound arms, Suzuki couplings were applied. The crucial introduction of the pyridine C-2 and C-6 substituents occurred by Fe(acac)₃-catalyzed alkylations (acac = acetylacetonate). The preparation of the C₃-symmetrical compound involved an alternating sequence of halogenations and coupling reactions. The self-assembly behavior of the four resulting star-shaped compounds at the interface between 1-phenyloctane and the basal plane of highly oriented pyrolytic graphite (HOPG) was studied by scanning tunnelling microscopy (STM). We found self-assembled monolayers with structures strongly dependent on the substitution patterns of the investigated compounds. The reduction of the symmetry from a D_3h- to a C_3h-symmetrical compound led to an entirely different self-assembly behavior with the change from a hexagonal to a lamellar arrangement.

A simple and flexible synthesis for a series of star-shaped pyridine, bipyridine, and terpyridine derivatives is reported by using a modular approach that combines the use of a ligand, spacer, and core unit. A fairly efficient method to prepare 4′-nonafloxy-functionalized terpyridine derivatives is described. The building blocks that contain the functionalized pyridine, bipyridine, or terpyridine derivatives were linked to different C₃-symmetrical core units. In most cases, Sonogashira reactions were employed in the crucial final steps of the synthesis. A star-shaped dodecafluorinated compound was also prepared in a straightforward fashion. A simple procedure for the preparation of partially silylated 1,3,5-triethynylbenzene derivatives is presented, which provides an approach to C₂-symmetrical star-shaped compounds that have only one terpyridine and two terphenyl units as “dummy” ligands. The absorption and emission spectra of the fully conjugated C₃-symmetrical pyridine derivatives were systematically investigated, and fairly large Stokes shifts were observed.

The 1,3-dipolar cycloadditions of ethyl 2-diazo-3,3,3-trifluoropropanoate with electron-rich and electron-deficient alkynes, as well as the van AlphenHüttel rearrangements of the resulting 3H-pyrazoles were investigated. These reactions led to a series of CF₃-substituted pyrazoles in good overall yields. Phenyl- and diphenylacetylene proved to be unreactive, but, at high temperature, the diazoalkane and phenylacetylene furnished a cyclopropene derivative. As expected, the 1,3-dipolar cycloaddition to the ynamine occurred much faster than those to electron-deficient alkynes. With one exception, all cycloadditions proceeded with excellent regioselectivities. The [1,5] sigmatropic rearrangement of the primary 3H-pyrazoles provided products with shifted acyl groups; products resulting from the migration of a CF₃ group were not detected. In agreement with literature reports, this rearrangement occurs faster with 3H-pyrazoles bearing electron-withdrawing substituents.

The total synthesis of the human telomerase inhibitor γ-rubromycin in its racemic form was accomplished in 3.8 % overall yield. The key feature of this synthesis is an efficient acid-catalyzed spiroketalization for the construction of the spiroketal core. The required electronically well-balanced spiroketal precursor was obtained by the convergent assembly of a naphthyl-substituted aldehyde, an α-methoxyallyl-γ-silyl-substituted phosphonate as the central C₃ building block, and a highly functionalized aryl Grignard reagent. Another key feature is the late-stage construction of the isocoumarin moiety and a simultaneous protodesilylation furnishing the known methyl aryl ether protected precursor of γ-rubromycin.

A versatile method for the synthesis of functionalized 2,2′:6′,2′′-terpyridines by assembly of the terminal pyridine rings is presented. The cyclization precursors—bis-β-ketoenamides—are prepared from 4-substituted 2,6-pyridinedicarboxylic acids and acetylacetone or its corresponding enamino ketone. Treatment with trimethylsilyl trifluoromethanesulfonate induces a twofold intramolecular condensation providing an efficient access to 4,4′′-di- and 4,4′,4′′-trifunctionalized 6,6′′-dimethyl-2,2′:6′,2′′-terpyridines. Using this method, hitherto unknown 4,4′′-bis(dimethylamino)- and 4,4′,4′′-tris(dimethylamino)terpyridines have been prepared that show remarkably high calculated Lewis basicities.

Der Telomeraseinhibitor γ-Rubromycin wurde in seiner racemischen Form in einer Gesamtausbeute von 3.8 % hergestellt. Der Schlüsselschritt der Synthesesequenz ist eine effiziente säurekatalysierte Spiroketalisierung unter Aufbau der zentralen Spiroketaleinheit. Die Synthese des erforderlichen, elektronisch ausbalancierten Spiroketalvorläufers erfolgte durch das konvergente Zusammenführen eines naphthylsubstituierten Aldehyds, eines α-Methoxyallyl-γ-silyl-substituierten Phosphonats als zentralem C₃-Baustein und eines hoch funktionalisierten Aryl-Grignard-Reagens. Ein weiteres Merkmal der Synthese ist eine späte Isocumarinbildung bei gleichzeitiger Protodesilylierung zu einem als Methylarylether geschützten γ-Rubromycin-Vorläufer.

meso-Substituted trans-A₂B₂-porphyrins bearing specific patterns of substituents are crucial building blocks in porphyrin-based biomimetic systems and molecular materials and can be used for the construction of well-defined porphyrin-based architectures. A new stepwise and rational synthesis of functionalized trans-A₂B₂-porphyrins is reported in which for the first time donor–acceptor-substituted cyclopropane precursors (d–a cyclopropanes) are exploited. The three presented d–a cyclopropanes are readily accessible in a multi-gram scale and serve as aldehyde equivalents in the reaction with an excess of pyrrole to afford the corresponding dipyrromethanes (DPMs). The three DPMs were synthesized in yields of 60–74%. They are stable in purified form in the absence of light and air and were subsequently condensed with a wide range of aliphatic and aromatic aldehydes bearing electron-donating or electron-withdrawing substituents followed by oxidation to form the corresponding trans-A₂B₂-porphyrins. Fourteen functionalized porphyrins were synthesized in yields of 14–31%, indicating the broad scope of the synthetic procedure. The possibility to introduce key functional groups is emphasized, which enables subsequent modification of these porphyrins with moieties inducing biological activity. Modification of the tetrapyrroles may occur by addition to one of the porphyrin peripheral double bonds, the use of substituents of the aryl groups or via the methoxycarbonyl group at two of the meso-substituents. Three examples of porphyrins were converted into the corresponding 7,8-dihydroxychlorins by osmium-mediated dihydroxylation and one of the resulting chlorins was subjected to saponification to give a highly polar chlorin dicarboxylic acid. A 4-bromophenyl-substituted d–a cyclopropane was prepared by rhodium-catalyzed cyclopropanation and then transformed into a DPM which was subsequently condensed to a porphyrin. Its Zn complex allowed a Heck reaction to afford the functionalized bis(alkenyl)-substituted trans-A₂B₂-Zn-porphyrin.

An approach to enantiopure 1,4-amino alcohols of type 4 by samarium diiodide mediated N–O cleavage of 3,6-dihydro-2H-1,2-oxazines 3 is presented. In several cases we observed the formation of 3-methoxypyrrole derivatives 5 as byproducts in significant amounts. For 1,2-oxazine derivative syn-3a, up to 27 % of pyrrole 5a was isolated. The examples presented show a strong dependence of the chemoselectivity on the structure of the precursor 1,2-oxazines. The formation of pyrroles 5 as side-products is rationalized by a competitive intramolecular hydrogen shift of the initially formed ring cleavage intermediate B to C and subsequent cyclization of aldehyde E to afford F. This pathway can be disfavoured when a higher excess of samarium diiodide was employed, which generally provided the 1,4-amino alcohols 4 in good yields.

Calix[4]phyrins are an important class of hybrid macrocyclic systems at the interface between porphyrins and calixpyrroles (porphyrinogens). A new stepwise synthesis of oxidation-resistant meso-hydrogenated calix[4]phyrins is reported, which allows variable substitution in the residues of their sp²-meso-centers without the need for a porphyrin intermediate. It relies on the acid-catalyzed condensation of a sterically hindered donor–acceptor-substituted cyclopropane precursor with pyrrole to form a sterically congested dipyrromethane. This was subsequently condensed with a wide range of alkyl and aryl aldehydes bearing electron-donating or electron-withdrawing substituents followed by an oxidation step to form stable calix[4]phyrin(1.1.1.1)s with bridging meso-CH hydrogen atoms through an acid-promoted dehydrative condensation. The methodology avoids any need for premetallation of the macrocycle and/or the use of organometallic catalysts or reagents and allows the incorporation of the bulky cyclopropane-derived substituents specifically into the 5,15-meso-like positions. The resulting regioisomerically pure products display conformational features that reflect their mixed nature between porphyrins and calixpyrroles and they were assessed by X-ray diffraction analysis, NMR techniques and UV/Vis spectroscopy. The possibility to introduce key functional groups enables subsequent modification of these calix[4]phyrins and allows their connection to other groups such as biologically active moieties. Of special interest is an unprecedented example of an acid-driven lactonization that results in the incorporation of a mono-meso-spirolactone into a calix[4]phyrin(1.1.1.1). Moreover, it is demonstrated that this approach to calix[4]phyrins is also applicable to other sterically congested dipyrromethanes.

This report describes the development of a first and second generation approach towards the synthesis of the ABCEG pentacyclic core structure of Strychnos alkaloids. First, we discuss a sequential approach applying a series of functional group transformations to prepare suitable precursors for cyclization reactions. These include attempts of samarium diiodide-induced cyclizations or a Barbier-type reaction of a transient lithium organyl, which successfully led to a tetracyclic key building block earlier used for the synthesis of strychnine. Secondly, we account our first steps towards the development of an atom-economical samarium diiodide-induced cascade reaction using “dimeric” indolyl ketones as cyclization precursors. In this context, we discuss plausible mechanisms for the samarium diiodide-induced cascade reaction as well as transformations of the obtained tetracyclic dihydroindoline derivatives.

Tripyrrolidinophosphoric acid triamide (TPPA) can replace carcinogenic HMPA as a Lewis basic additive in many reactions involving samarium ketyls. In most cases, yields and selectivities of cyclizations of (het)aryl, alkenyl, and alkynyl ketones are similar. TPPA is also a good substitute of HMPA in the O-silylation of an ester enolate and in reactions oflithiated 1,3-dithiane. All these results clearly demonstrate that in many cases the use of HMPA can be avoided.

Enantiopure 3,6-dihydro-2H-1,2-oxazines were prepared by [3+3] cyclisations starting from lithiated methoxyallene and the L-erythrose-derived nitrones 1′ and 3. The role of the side-chain protective group, which steers the highly selective formation of either anti- or syn-configured products, was demonstrated. A hydroboration/oxidation protocol smoothly converted 1,2-oxazine derivative syn-5 into secondary alcohol 6. After deprotection, polyhydroxylated tetrahydro-2H-1,2-oxazine 11, which can be regarded as an azasugar, was isolated. Analogous treatment of 1,2-oxazine anti-5 with the borane not only provided the expected secondary alcohol 7, but it also induced reduction of the C=C bond and ring opening. Treatment of syn-5 and anti-2 with hydrochloric acid in methanol induced deprotections and cyclisations leading to bicyclic tetrahydro-2H-1,2-oxazine derivatives. The second ring can be either a furan or a pyran ring. In the syn series, furan derivative 12 was formed exclusively, and its hydrogenolysis led to enantiopure aminofuran derivative 14. Acid-promoted rearrangement of unprotected anti-2 led to a mixture of bicyclic compounds with furan or pyran rings fused to the 1,2-oxazine core. However, when TBDPS-protected compound 20 was used it cleanly led to 1,2-oxazine 21 with a fused furan ring and then to aminofuran 22. Alternatively, the N–O bond in unprotected anti-2 was chemoselectively reduced with samarium diiodide, efficiently generating highly functionalized allylic alcohol 23. Acid-promoted cyclisation and deprotection furnished furan derivative 24. Mechanistic suggestions to explain the different outcomes of the acid-induced transformations are provided. Overall, it is demonstrated that the stereodivergent addition of lithiated alkoxyallenes to L-erythrose-derived nitrones allow flexible access to a series of enantiopure amino polyols, including aminofuran derivatives.

During attempts to prepare functionalized 5-iodopyridine derivatives the unexpected formation of iodo[1,3]dioxolo[4,5-c]pyridines was discovered. The conversion of 3-alkoxypyridin-4-ols into the corresponding 5-iodo compounds was achieved by reaction with one equivalent of iodine or tetramethylammonium dichloroiodate under basic conditions. When three equivalents of iodine were used in chlorinated solvents, after 5-iodination, subsequent reaction of the 3-alkoxy group took place to form a 1,3-dioxolane ring with the 4-hydroxyl group. Generation of the resulting iodo[1,3]dioxolo[4,5-c]pyridines is explained by a radical process known as the Hofmann–Löffler–Freytag reaction. Two 6-ethynylpyridine derivatives were examined in the iodination process to establish a route to pyridine-containing macrocycles. The pentasubstituted 5-iodopyridine derivative 21 could be prepared; however, attempts to achieve cyclotrimerization of this building block under different conditions were not successful. Reaction of 21 with copper chloride allowed isolation of a copper acetylide 22, which aggregates to a triangular trimeric complex containing four copper(I) ions such as [23·Cu]⁺ as monitored by ESI mass spectrometry.

Rh₂(OAc)₄-Catalyzed decomposition of diazo esters in the presence of perfluoroalkyl- or perfluoroaryl-substituted silyl enol ethers smoothly provided the corresponding alkyl 2-siloxycyclopropanecarboxylates in very good yields. The generated donoracceptor cyclopropanes are equivalents of γ-oxo esters, which we demonstrated by their one-pot transformations to yield fluorine-containing heterocycles. A reductive procedure selectively afforded perfluoroalkyl-substituted γ-hydroxy esters or γ-lactones. The treatment of the donoracceptor cyclopropanes with hydrazine or phenylhydrazine afforded a series of perfluoroalkyl- and perfluoroaryl-substituted 4,5-dihydropyridazin-3(2H)-ones.

A simple procedure for the synthesis of enantiopure hydroxymethyl-substituted pyridine derivatives is presented. The developed method is based on TMSOTf-promoted cyclocondensations of β-ketoenamides, leading to differently substituted 4-hydroxypyridine/4-pyridone derivatives. The required β-ketoenamides were prepared by acylation ofeasily available enamino ketones with suitably protected enantiopure carboxylic chlorides. Most of the experiments were performed with D-mandelic acid as starting material. It has been shown that all steps occur essentially without racemisation. Several of the prepared 4-pyridone derivatives were transformed into the corresponding pyrid-4-yl nonaflates and subjected to a series of palladium-catalysed transformations, such as Suzuki, Heck or Sonogashira reactions. In addition, regioselective side-chain functionalisation of unsymmetrically 2,6-disubstituted pyridine derivatives was accomplished by application of Boekelheide rearrangements of the corresponding pyridine N-oxides. The presented methods allow a flexible, rapid and scalable approach to highly substituted, enantiopure pyridine derivatives.

In this report we describe the synthesis of differentially functionalized pyridine derivatives 3 and the related 3-bromo-substituted pyridines 11. Dissociation of 6H-1,2-oxazine precursors (1a, 1b, 5, 6, or 12) in situ, mediated by boron trifluoride–diethyl ether, generates the azapyrylium intermediates A, which undergo hetero-Diels–Alder reactions with various mono- and disubstituted alkynes 2. In general, these pyridine syntheses proceeded with high efficiencies and were very flexible with respect to all positions in the pyridine cores. For the 3-phenyl-substituted pyridine derivatives 3a–3j and 11a–11f the best results were obtained by a new microwave-assisted protocol, which is clearly superior to the previously used conventional procedure at low temperature in dichloromethane. Furthermore, 3-(trifluoromethyl)- and 3-acryloyl-substituted 6H-1,2-oxazines reacted cleanly under microwave irradiation conditions to furnish the expected pyridine derivatives 3k and 3l in respectable yields. The 3-bromo-substituted pyridines 11 were further functionalized through palladium-catalyzed couplings such as Suzuki or Sonogashira reactions, which led smoothly to tri- or tetrasubstituted pyridine derivatives such as 19–21 and 23. Reductive debromination of 11e afforded the pyridine 17 in excellent yield, whereas oxidation of the pyridinyl thioether 3g with oxone led to the corresponding sulfoxide 24. Our method thus establishes a new and versatile approach to highly substituted pyridine derivatives.

Starting from enantiopure 3,6-dihydro-2H-1,2-oxazinessyn-1 we introduced an additional hydroxy group in a stereoselective fashion by a standard hydroboration/oxidation protocol. Under “regular“ conditions substrate control was sufficient to achieve a very high degree of stereoselectivity. However, a diastereomeric product was isolated when a partially “degraded” borane reagent was used. We could synthesise this new diastereomer on purpose by addition of alcohols to the “fresh“ hydroboration reagent. The level of stereoinduction increased with the steric bulk of the added alcohol: MeOH < nBuOH < iPrOH < tBuOH. After a two-step oxidation/reduction sequence, another 5-hydroxy-1,2-oxazine epimer was accessible. The obtained 5-hydroxy-1,2-oxazine diastereomers 2 were used as versatile intermediates in a series of transformations leading to several amino polyol derivatives. Complete deprotection of both diastereomers without cleavage of the N–O bond led to the novel polyhydroxylated tetrahydro-2H-1,2-oxazines 3 and epi-3. By change of the deprotection conditions the open-chain amino polyol 4 with D-iditol configuration became accessible. In an alternative sequence 5-hydroxy-1,2-oxazines were utilised to synthesise imino sugars (polyhydroxylated pyrrolidines). Samarium diiodide induced cleavage of the 1,2-oxazine N–O bond furnished 1,4-amino alcohols, which were cyclised to give the corresponding pyrrolidine derivatives after activation by mesyl chloride. This sequence either led to a 3-methoxy-substituted trihydroxylated pyrrolidine derivative or to the related fully deprotected compound.

Herein, we describe our attempts to systematically prepare a series of oligo(2-thienyl)-substituted pyridine derivatives. The crucial starting material, a β-alkoxy-β-ketoenamide, is easily available on a large scale by the reaction of lithiated methoxyallene with thiophene-2-carbonitrile and thiophene-2-carboxylic acid. This three-component reaction is followed by intramolecular cyclization to yield the suitably functionalized 2,6-di(2-thienyl)-substituted pyridine derivates. The two oxygen atoms allow the programmed activation of positions C-3, C-4, or C-5 of the pyridine ring to perform palladium-catalyzed coupling reactions with thiophene-2-boronic acid or 2-(tributylstannyl)thiophene, and alternatively, reductive removal of groups. With this concept, we were able to prepare five pyridine derivatives with 2-thienyl substituents in the 2,6-, 2,3,6-, 2,4,6-, 2,3,4,6-, and 2,3,5,6-positions. 2,3,4,5,6-Penta(2-thienyl)pyridine was not available with our methods. The UV/Vis and fluorescence spectra of all pyridines were recorded and showed a dependence on the substitution pattern and protonation state. For the protonated 2,3,5,6-tetra(2-thienyl)-substituted pyridine, a Stokes shift of about 180 nm with an emission at 515 nm was observed.

This comprehensive study describes our results of samarium diiodide induced 5-exo-trig to 8-exo-trig cyclization/alkylation sequences of 3′-acceptor-substituted indolyl ketones. All cyclization precursors were easily prepared by simple N-alkylation or N-acylation of indole derivatives with the corresponding iodo alkanones, acid chlorides, or lactones. After treatment of indolyl ketones with two equivalents of SmI₂, the generated stabilized carbanionic intermediates were trapped with different electrophiles leading to a variety of highly substituted indoline derivatives in good to very good yields. In general, the cyclization products were obtained as single diastereomers bearing a newly generated quaternary center, a common structural motif in various indole alkaloids. The relative configurations of the products were established by NOE experiments and by single-crystal analysis and follow the rules already established. Furthermore, the obtained products were subjected to a series of chemical transformations, such as oxidation, reduction, and metathesis reactions resulting in a range of interesting synthetic building blocks valuable for further applications.

Lithiated alkoxyallenes, nitriles, and carboxylic acids have been employed as precursors in a three-component reaction leading to highly substituted β-alkoxy-β-ketoenamides. Upon treatment with trifluoroacetic acid, these enamides could be easily cyclized to 5-acetyloxazole derivatives. The synthesis is very flexible with respect to the substitution pattern at C-2 and C-4 of the oxazole core. A mechanistic suggestion for the oxazole formation is presented on the basis of ¹⁸O-labeled compounds and their mass spectrometric analysis. In several cases, 1,2-diketones are formed as side products or even as major components. The acetyl moiety at C-5 of the oxazole derivatives can efficiently be converted into alkenyl or alkynyl moieties, which allows a multitude of subsequent reactions. Condensation reactions of the acetyl group provided the expected oxime or hydrazone. By applying a Fischer reaction, the phenylhydrazone could be transferred into an indole, which emphasizes the potential of 5-acetyloxazoles for the preparation of highly substituted (poly)heterocyclic systems. The alkynyl group at C-2 is prone to addition reactions, providing an enamine with interesting photophysical properties. Sonogashira couplings were performed with 5-alkynyl-substituted oxazoles, furnishing the expected aryl-substituted products. This alkynyl unit was employed for the preparation of a new, star-shaped trisoxazole derivative. The ability of this multivalent compound to form self-assembled monolayers between the basal plane of highly oriented pyrolytic graphite and 1-phenyloctane was demonstrated by scanning tunneling microscopy (STM). The star-shaped compound seems to prefer the C₃-symmetric arrangement in this two-dimensional crystal. Two 1,2-diketones were smoothly converted into functionalized quinoxaline derivatives.

The synthesis of a new class of cyclic peptidomimetics containing 5-aminothiophene subunits in their backbone is presented. A modified Gewald reaction was applied as a key step in the synthesis of the thiophene amino acid that was used as a building block in the synthesis of linear oligomers by using standard peptide coupling protocols. Macrocyclization was achieved under high dilution by using EDCI as a coupling reagent. The conformations of an acyclic dimer and a cyclic tetramer were determined by X-ray crystallographic analyses.

A series of highly substituted β-alkoxy β-keto enamides were prepared by a multi-component reaction combining lithiated alkoxyallenes, nitriles and carboxylic acids. Apt conditions were developed for their conversion into 5-alkoxypyrimidine derivatives. This synthesis is highly flexible with respect to the substitution pattern at C-2 and C-4 of the pyrimidine core. The corresponding pyrimidin-5-yl nonaflates allowed subsequent transformations at C-5 by palladium-catalyzed couplings such as Sonogashira and Suzuki reactions. The Sonogashira coupling of a pyrimidinyl alkyne with a pyridinyl nonaflate and a subsequent cyclization led to an efficient access to pyrimidinyl-substituted furo[2,3-c]pyridine derivatives. The C-6 methyl group which is present in all of the prepared pyrimidines can easily be converted into formyl, carboxylic or alkynyl moieties which allow the synthesis of additional pyrimidine derivatives.

Here we summarise our results for SmI₂-induced 5-exo-trig to 8-exo-trig reductive cyclisations of suitably substituted indole and pyrrole derivatives. All precursors were easily prepared by simple N-alkylation or N-acylation of indole and pyrrole derivatives with the corresponding iodo alkanones, acid chlorides or lactones. The SmI₂-induced cyclisations in most cases provided tri- and tetracyclic derivatives, even in the absence of HMPA, in good to very good yields and with excellent diastereoselectivities. Extensive investigations of the reaction conditions revealed that in the presence of different proton sources SmI₂-induced cyclisations afforded mainly one major type of diastereomer (thermodynamic control), so the formation of three or four stereogenic centres is controlled in one step. The mechanism of the SmI₂-induced ketyl coupling is discussed in more detail on the basis of these observations and two possible mechanistic pathways are compared. The assumed intermediate samarium enolates were also trapped with allyl iodide, furnishing interesting polycyclic N-heterocycles bearing newly formed quaternary centres as single diastereomers.

Stereodefined oxygen-substituted 1,2-oxazines were prepared by three different routes. The cycloaddition of enol ethers such as 1 with α-nitrosoalkenes generated in situ gave the heterocycles 3 and 4. Acid-catalysed additions of alcohols to the 6H-1,2-oxazines 5 led to mixtures of the adducts 6 and the substitution products 7 with moderate chemoselectivity. Epoxidation of the 6H-1,2-oxazines 5 proceeded more efficiently and furnished the corresponding epoxides 25 and 32 in reasonable to excellent yields. It was demonstrated that the resulting oxygen-substituted 1,2-oxazines were suitable precursors for the preparation of cyclic or acyclic primary and secondary amines in racemic or enantiopure form. Hydrogenation of the 3-phenyl-substituted 1,2-oxazines 3 and 25a and of (6S)- and (6R)-32 preferentially furnished the 1,2-amino alcohols 15, rac-29 and (2S)- and (2R)-29. On the other hand, reduction of the 3-ethoxycarbonyl-substituted 1,2-oxazines 4, 6d and 20 led to the formation of the N-protected proline esters 21–24 in moderate yields. It was also found that the 5-methyl-6H-1,2-oxazine 10 was a good precursor for the propargylic ether 11, which allowed a Pauson–Khand reaction leading to the tricyclic compounds 13 and 14. Hydrogen peroxide converted 10 into a hydroperoxide intermediate, which was further transformed into the 1,2-oxazin-6-one 28b. Overall, the results demonstrate the remarkable potential of suitably substituted 1,2-oxazine derivatives for the stereoselective synthesis of amines.

A stereodivergent synthesis of differently configured C2-branched 4-amino sugar derivatives was accomplished. The Lewis acid mediated rearrangement of phenylthio-substituted 1,2-oxazines delivered glycosyl donor equivalents that can directly be employed in glycosidation reactions. Treatment with methanol provided internally protected amino sugar equivalents that have been transformed into the stereoisomeric methyl glycosides 28, ent-28, 29, ent-29 and 34 in two simple reductive steps. Reaction with natural carbohydrates or bicyclic amino sugar precursors allowed the synthesis of homo-oligomeric di- and trisaccharides 44, 46 and 47 or a hybrid trisaccharide 51 with natural carbohydrates. Access to a bivalent amino sugar derivative 54 was accomplished by reaction of rearrangement product 10 with 1,5-pentanediol. Alternatively, when a protected L-serine derivative was employed as glycosyl acceptor, the glycosylated amino acid 60 was efficiently prepared in few steps. In this report we describe the synthesis of unusual amino sugar building blocks from enantiopure 1,2-oxazines that can be attached to natural carbohydrates or natural product aglycons to produce new natural product analogues with potential applications in medicinal chemistry.

How much fluoride is good for a strong electron-withdrawing effect? In this review we summarize recent results on the use of perfluoroalkanesulfonates, in particular of the cost effective nonafluorobutanesulfonates (nonaflates), in transition metal-catalyzed reactions and a few other typical transformations. During the last decade many advantages over the commonly used triflates have been discovered. The generation of alkenyl and (het)aryl nonaflates and their applications in metal-catalyzed processes such as Heck, Suzuki, Sonogashira, Stille, and Negishi couplings or amination reactions are described. Although far from a systematic investigation, all the presented results clearly demonstrate the many advantages of nonaflates and of similar higher fluorinated sulfonates in laboratory and industrial scale organic synthesis.

Starting from lithiated methoxyallene and lactaldehyde derivatives, the four rare 2,6-dideoxy-hexoses L-cymarose, L-sarmentose, L-diginose and L-oleandrose were synthesized in a stereodivergent fashion. Key steps towards these four target monosaccharides were the oxidative ring openings of allene-derived 2,5-dihydrofurans, diastereoselective carbonyl reductions as well as face-selective hydrogenation protocols. First glycosylation reactions employing thiophenyl glycosyl donors of L-cymarose and L-diginose were performed in high yields and with fair to excellent stereocontrol. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

Lewis acid promoted rearrangements of different 4-alkoxy-substituted 1,2-oxazines syn-1 are reported. Depending on the nature of this alkoxy group different reaction pathways are possible either providing bicyclic 1,2-oxazinones 2 or the novel tricyclic products 3–5. A mechanistic rational describing the role of the 4-alkoxy group is presented. The key step for formation of tricyclic skeletons 3–5 is a 1,2-alkyl shift. Hydrogenation reactions of these tricyclic compounds gave unsaturated 1,2-oxazines 12 and 13 or tetrahydrofurans 15a–c/16a–c depending on the time of hydrogenolysis. Tetrahydrofuryl-annulated 1,2-oxazine 12 was used for further transformations into complex substituted tetrahydrofurans. Reduction with sodium cyanoborohydride and subsequent cleavage of the N,O-bond by hydrogenation furnished aminofuran derivative 19. Alternatively treatment with a strong base such as n-butyllithium afforded imidoester 21 via a Beckmann-type fragmentation.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)

1,3-Dioxolanyl-substituted 1,2-oxazines, such as syn-1 and anti-1, rearrange under Lewis acidic conditions to provide bicyclic products 2–5. Subsequent reductive transformations afforded enantiopure 3-aminopyran derivatives such as 7 and 9 or their protected diastereomers 16 and 18, which can be regarded as carbohydrate mimetics. An alternative sequence of transformations including selective oxidation of the primary hydroxyl groups in 21 and 24 led to two protected β-amino acid derivatives with carbohydrate-like backbone (sugar amino acids). Treatment of bicyclic ester 23 with samarium diiodide cleaved the NO bond and furnished the unusual β-lactam 27 in excellent yield. Alternatively, γ-amino acid derivative 29 was efficiently prepared in a few steps. Fairly simple transformations gave azides 32 and 35 or alkyne 30 which are suitable substrates for the construction of oligosaccharide mimetics such as 34 by copper iodide catalyzed cycloadditions. With this report we demonstrate that enantiopure rearrangement products 2–5 are protected precursors of a variety of polyfunctionalized pyran derivatives with great potential for chemical biology.

Treatment of naphthyl-substituted cyclopentane-1,3-diones with the samarium diiodide- hexamethylphosphoramide (HMPA) complex in the presence of tert-butyl alcohol provided the expected tetracyclic diols with steroid-like structures. Surprisingly, reactions without the proton source led to the efficient formation of a new pentacyclic diol. In this case the toxic additive HMPA could be substituted by a combination of lithium bromide (in situ generation of samarium dibromide) and N,N-dimethylimidazolidone. The styrene-like alkene moiety of this product was used to prepare an ensemble of highly substituted pentacyclic steroid-like compounds.

We report the synthesis of a series of 2,6-disubstitutedpyridines in a straightforward manner starting from readily available 2-substituted pyridines. The main sequence involves a selective α-lithiation reaction with halogen functionalization followed by a Grignard reaction catalyzed by Fe(acac)₃. After demonstration of the easy feasibility of this strategy by synthesizing 2,6-disubstituted pyridines 1, the route was applied to obtain pyridine derivatives bearing electron-donating or electron-withdrawing groups. Thus, a series of pyridines bearing an aryl moiety in the 6-position and an alkyl chain in the 2-position was obtained. The pyridines were studied for their self-assembly abilities at the interface between an organic solution and the basal plane of graphite. Preliminary STM results for one compound are reported.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

The siteselectivity of cycloadditions of the D-glyceraldehyde-derived nitrone 1 and methoxyallene (2) is strongly influenced by Lewis acids. The uncatalyzed reaction results in the formation of isomeric isoxazolidines 3a–3d and 4a–4c, whereas in the presence of different Lewis acids exclusive formation of 4-methylene-substituted isoxazolidines 4a–4d is observed. Furthermore, the diastereofacial selectivity of the methoxyallene addition to nitrone 1 can be controlled, thus giving rise to both diastereomeric isoxazolidines 3,4′-anti-4 or 3,4′-syn-4, just by employing different Lewis acids. The redox ring-opening of isoxazolidines 4 using Murahashi's protocol yields α-methylene-β-amino acid esters 5a,b and 7a,b.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

In this report, we describe our experiments dealing withsamarium diiodide promoted cyclizations of quinolyl-substituted ketones 6–12 and also the attempted reductive cyclization of carbazole-containing ketone 13. These precursors were prepared by Heck-type coupling reactions of the corresponding hetaryl nonaflates with adequately substituted olefins as a key step. The cyclization of compounds 7–12 led to nitrogen-containing tri- and tetracyclic compounds 23–28 in moderate to good yields and generally proceeded in a highly diastereoselective fashion. The azatetracycles present steroid-like skeletons but with unnatural cis–cis annulation of rings B, C and D. We also describe the chemical modification of the styrene-type double bond of these products, which provided highly functionalized steroid-type compounds such as 29, 30 and 32.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

A series of 4-pyridyl nonaflates was coupled with several terminal alkynes to efficiently provide new 4-alkynyl-substituted 3-alkoxypyridine derivatives. Apt conditions were developed for their conversion into furo[2,3-c]pyridines. Sonogashira reactions of 4-alkoxy-substituted 3-pyridyl nonaflates allowed an access to regioisomeric furo[3,2-c]pyridines. For both types of alkynyl-substituted alkoxypyridinesan alternative method for cyclization employing iodine monochloride furnished iodinated furo[2,3-c]- or furo[3,2-c]pyridines, which can undergo a second palladium-catalyzed step. Iodination of 4-hydroxypyridine derivative 24 with iodine afforded a pentasubstituted pyridine which after Sonogashira reaction immediately undergoes a cyclization to furo-pyridine 25. Thus, three different types of furo-pyridines can be prepared starting from one precursor. Several compounds prepared are fluorescent and show strong Stokes shifts. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

This comprehensive study describes the influence of substituents at the aryl moiety on SmI₂-mediated intramolecular ketyl–aryl coupling reactions. Differently substituted γ-aryl ketones were employed as precursors, which were directly prepared by Heck reactions of 4-penten-2-ol with the corresponding bromo- or iodobenzenes. After treatment with two equivalents of samarium diiodide γ-aryl ketones bearing electron-withdrawing substituents such as cyano, trifluoromethyl or carbonyl groups gave the expected hexahydronaphthalene derivatives as single diastereoisomers in most cases. The position of the substituents was also of crucial influence on the outcome; in several cases ipso-substitution leading to the formation of spiro compounds was observed. Electron-donating substituents at the aromatic moiety are less favourable for the ketyl–aryl couplings. They apparently impede the second electron transfer that is involved in this multi-step process. On the basis of these observations the mechanism of the SmI₂-promoted ketyl–aryl couplings is discussed in detail. For precursors with electron-withdrawing substituents in m-position fairly stabilized carbanionic intermediates of the SmI₂-promoted cyclization could be trapped with acetone or allyl bromide as electrophiles to regioselectively provide the corresponding addition products. Our results should be valuable for synthetic applications of the stereoselectively generated hexahydronaphthalene derivatives.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)