bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural and Photophysical Properties of Pseudo‐Tricapped Trigonal Prismatic Lanthanide building blocks controlled by zinc(II) in heterodinuclear df complexes
Authors: Piguet Claude , Rivara‐Minten Elisabeth , Hopfgartner Gérard , Bünzli Jean‐Claude G.
Published: December 2004

An efficient combination of electrospray mass spectrometry (ES‐MS), spectrophotometric and 1H‐NMR titrations in solution is used to characterize the assembly of the segmental ligand 2‐{6‐[1‐(3,5‐dimethoxybenzyl)‐1H‐benzimidazol‐2‐yl]pyridin‐2‐yl}‐1, 1′‐dimethyl‐5,5′‐methylene‐2′‐(5‐methylpyridin‐2‐yl)bis[1H‐ benzimidazole] (L2) with ZnII and 4f metal ions, LnIII. Ligand L2 reacts with Zn(ClO4)2 in MeCN to give successively [Zn(L2)2]2+, where the metal ion is coordinated by the tridentate binding units of the ligands, and the double‐helical head‐to‐head complex [Zn2(L2)2]4+. When L2 reacts with Ln(ClO4)3 (Ln = La, Eu, Lu), LaIII only leads to a well‐defined cylindrical C1‐symmetrical homodinuclear head‐to‐tail complex [La2(L2)3]6+ in solution, while chemical‐exchange processes prevent the 1H‐NMR characterization of [Eu2(L2)3]6+, and LuIII gives complicated mixtures of complexes. However, stoichiometric amounts of LnIII (Ln = La, Ce, Pr, Nd, Sm, Eu, Tb, Y, Lu), ZnII, and L2 in a 1:1:3 ratio lead to the selective formation of the C3‐symmetrical heterodinuclear complexes [LnZn(L2)3]5+ under thermodynamic control. Detailed NOE studies show that the ligands are wrapped about the C3 axis defined by the metal ions, and the separation of dipolar and contact contributions to the 1H‐NMR paramagnetic shifts of the axial complexes [LnZn(L2)3]5+ (Ln = Ce, Pr, Nd, Sm, Eu) in MeCN establishes that ZnII occupies the pseudo‐octahedral capping coordination site defined by the three bidentate binding units, while LnIII lies in the resulting ‘facial’ pseudo‐tricapped trigonal prismatic site produced by the three remaining tridentate units. Photophysical measurements show that [LnZn(L2)3]5+ (Ln = Eu, Tb) are only weakly luminescent because of quenching processes associated with the C3‐cylindrical structure of the complexes. The use of 3d metal ions to control and design isomerically pure ‘facial’ tricapped trigonal prismatic lanthanide building blocks is discussed together with the calculation of a new nephelauxetic parameter associated with heterocyclic N‐atoms coordinated to LnIII.
Pyranosyl‐RNA (‘p‐RNA’): Base‐pairing selectivity and potential to replicate. Preliminary communication
Authors: Pitsch Stefan , Krishnamurthy Ramanarayanan , Bolli Martin , Wendeborn Sebastian , Holzner Armin , Minton Mark , Lesueur Catherine , Schlönvogt Irène , Jaun Bernhard , Eschenmoser Albert
Published: December 2004

Base pairing in p‐RNA (β‐D‐ribopyranosyl‐(4′ → 2′)‐oligonucleotides) is not only stronger than in DNA and RNA, but also more selective in the sense that it is strictly confined to the Watson‐Crick mode. Homopurine sequences (tested up to decamers) exist as single strands under conditions where they undergo reverse‐Hoogsteen self‐pairing in homo‐DNA or Hoogsteen self‐pairing in DNA. This exceptional pairing selectivity is rationalized as hinging on two structural features of p‐RNA: the large inclination between backbone axis and base‐pair axes in p‐RNA duplexes, and the higher rigidity of the p‐RNA backbone compared with RNA, DNA, and homo‐DNA. The most important consequence of the pairing selectivity refers to the potential of p‐RNA to replicate. Replicative copying of sequence information by nonenzymatic template‐controlled ligation is not hampered by self‐pairing of guanine‐rich templates, as it is known to be the case in the RNA series. We have demonstrated two replicative cycles in which G‐rich p‐RNA‐octamer templates induce sequence‐selective ligation of tetramer‐2′‐phosphate derivatives to complementary C‐rich octamer sequences, and in which the latter, with comparable efficiency, induce corresponding ligation reactions back to the original G‐rich octamers. Ligation is most satisfactorily achieved after pre‐activation of the 2′‐phosphate groups as 2′,3′‐cyclophosphate derivatives; in this version, the process does not proceed as oligocondensation, but as a genuine oligomerization. This is of considerable promise for the search for potentially natural conditions under which homochiral p‐RNA strands might self‐assemble and self‐replicate.
Preparation of the PdCl2 Complex of TADDOP, the Bis(diphenylphosphinite) of TADDOL: Use in enantioselective 1,3‐diphenylallylations of nucleophiles and discussion of the mechanism
Authors: Seebach Dieter , Devaquet Edmée , Ernst Alexander , Hayakawa Michiya , Kühnle Florian N. M. , Bernd Schweizer W. , Weber Beat
Published: December 2004

Reaction of the tartrate‐derived diol (R,R)‐α,α,α′,α′‐tetraphenyl‐2,2‐dimethyl‐1,3‐dioxolane‐4,5‐dimethanol (TADDOL) with chlorodiphenylphosphane gives a new bis(diphenylphosphanyl) ligand (TADDOP). The complex 4 formed with PdCl2 has been crystallized and its structure determined by X‐ray diffraction (Fig.1). The complex is used for Pd‐catalyzed enantioselective 1,3‐diphenylallylations of various nucleophiles which give products with enantiomer ratios of up to 88:12 (Scheme 2). Crystallization procedures lead to the enantiomerically pure (> 99:1) product 11 derived from dimethyl malonate. The structure of the TADDOP complex 4 is compared with those of other transition‐metal complexes containing chelating bis(diphenylphosphanyl) ligands (Fig.2). A crystallographic data base search reveals that the structures of transition‐metal complexes containing two Ph2P groups (superpositions in Fig.3) fall into one of two categories: one with approximate C2 symmetry and the other with C1 symmetry (20 and 19 examples, resp.). A mechanistic model is proposed which correlates the conformational chirality (δ or λ) of the four Ph groups' arrangement in such complexes with the topicity of nucleophile approach on Pd‐bound trans,trans‐1,3‐diphenylallyl groups (Scheme 3 and Table).
Multiple Cyclopropanations of C70. Synthesis and characterization of bis‐, tris‐, and tetrakis‐adducts and chiroptical properties of bis‐adducts with chiral addends, including a recommendation for the configurational description of fullerene derivatives with a chiral addition pattern
Authors: Herrmann Andreas , Rüttimann Markus , Thilgen Carlo , Diederich François
Published: December 2004

The regioselectivity of multiple cyclopropanations of C70 with 2‐bromopropanedioates in the presence of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) as base (Bingel reaction) was investigated in a systematic study. Bisadduct formation occurred preferentially at the 66 bonds formed by the most pyramidalized sp2‐C‐atoms at the two opposite poles of the fullerene and, in the reaction with achiral bis[(ethoxycarbonyl)methyl]2‐bromopropanedioate (13a), yielded three constitutionally isomeric bis(methano)fullerenes (Scheme 2). Two of them, C2‐symmetrical (±)‐1 and (±)‐2, are chiral; a fact which had not been considered in previous investigations. Formation of the third, C2v‐symmetrical isomer 3 was observed for the first time. Configurational descriptions for fullerene derivatives which possess a chiral chromophore as a result of specific functionalization patterns are proposed. Cyclopropanations of C70 with optically active bis[(S)‐1‐phenylbutyl] 2‐bromopropanedioate (13b) yielded five optically active, C2‐symmetrical bis‐adducts 7–11 which could be separated by preparative HPLC and fully characterized (Scheme 3, Fig.4). Compounds 7/8 and 9/10 represent two constitutionally isomeric pairs of diastereoisomers, and their circular dichroism (CD) spectra show pronounced Cotton effects mainly due to strong chiroptical contributions from the chirally functionalized fullerene chromophores (Fig.7). Since the addition patterns on the fullerene surface in each pair of diastereoisomers have an enantiomeric relationship, their CD spectra closely resemble those expected for two enantiomers. In the third constitutional isomer 11, the addition pattern on the fullerene surface is C2v‐symmetrical, and optical activity only results from the chiral addends. Its CD spectrum shows weak Cotton effects mainly from induced circular dichroism originating from the perturbation of the achiral fullerene chromophore by the attached chiral addends. Addition of diethyl 2‐bromopropanedioate (2 equiv.) to the C2‐symmetrical racemic bis‐adduct (±)‐2 yielded a mixture of tris‐adducts and one major, C2‐symmetrical tetrakis‐adduct (±)‐4 which was isolated in pure form (Scheme 4). Starting from the achiral C2v‐symmetrical bis‐adduct 3, one single Cs‐symmetrical tris‐(5) and one C2v‐symmetrical tetrakis‐adduct (6) were obtained as major products which were isolated and fully characterized (Scheme 5). The regioselectivity for introduction of a second addend in the same hemisphere of C70 is high and resembles the preferred pattern of bis‐addition seen in the functionalization of C60.
Synthesis and Evaluation as Glycosidase Inhibitors of 1H‐Imidazol‐2‐yl C‐Glycopyranosides
Authors: Granier Thierry , Vasella Andrea
Published: December 2004

The (1H‐imidazol‐2‐yl)ulose 8 and the 1H‐imidazol‐2‐yl C‐glycopyranosides 23 and 24 have been prepared from tetra‐O‐benzylgluconolactone 6 in two and six steps, respectively. The imidazoles 8 and 24 are moderate competitive inhibitors of sweet‐almond β‐glucosidase (pH 6.8, Ki ≈ 0.79 and 0.64 mM, respectively), while 23 is a competitive inhibitor of yeast α‐glucosidase (pH 6.8, Ki ≈ 0.26 mM). Addition of 2‐lithiated 1‐[(dimethylamino)methyl]‐1H‐imidazole to 6 gave the ulose 7 (68%), which was deprotected to 8. Reduction of 7 with NaBH4 yielded a 12:88 mixture 10/11. Attempts to selectively mesylate HOC(1) of these diols failed, while dinitrobenzoylation led to 19/20, which cyclized easily (NaH) to a 25:75 mixture of 21 and 22 which were separated and debenzylated to the C‐glycosides 23 and 24.
From Epiraikovenal, an Instrumental Niche‐Exploitation Sesquiterpenoid of Some Strains of the Marine Ciliated Protist euplotes raikovi, to an unusual intramolecular tele‐dienone‐olefin [2+2] photocycloaddition
Authors: Guella Graziano , Pietra Francesco , Dini Fernando
Published: December 2004

It is shown that strains of the marine ciliate Euplotes raikovi are subtly variable in their production of secondary metabolites. Strains GA8 and 39W from Mediterranean and SB8 from Californian coasts produce the sesquiterpenoid epiraikovenal (3), while strains GA8 and SB8 also produce secoepiraikovenal (4), which play an instrumental niche‐exploitation role and have also taxonomic significance. Comparison of 3 and 4 with raikovenal (2) and its putative biogenetic precursor 1, which have similar roles in the conspecific strain Morl from Casablanca coast in the Atlantic Ocean, inspired us the first case of intramolecular tele‐dienone‐olefin [2+2] photocycloaddition, exemplified here by the transformation of 1 into ent‐3. This served also to unequivocally clarify the stereochemical relationship between 3 and 2.
Neighboring‐Group Participation in the Gas Phase. Loss of benzaldehyde from [(benzyloxy)methyl]dialkylsilyl‐substituted 1,3‐dithianes
Authors: Fässler Jürg , Huber Priska , Bratovanov Svetoslav , Bigler Laurent , Bild Norbert , Bienz Stefan
Published: December 2004

[(Benzyloxy)methyl]dialkylsilyl‐substituted 1,3‐dithianes show in CI‐MS an abundant loss of benzaldehyde from the [M + H]+ quasi‐molecular ion. The fragmentation is explained with an intramolecular redox process, where a hydride is proposed to be transferred from the benzyl position to a neighboring thionium ion. This would form a particle that could readily lose benzaldehyde as a neutral fragment. The CI‐MS results provide an explanation for the unusual instability of (benzyloxy)methyl‐substituted silanes towards acids. In fact, the formation of benzaldehyde was established in the decomposition of a (benzyloxy)methyl‐substituted acylsilane in the presence of Lewis or Brønsted acids and ethanethiol. The CI‐MS study, therefore, represents a useful method to recognize unusual reactions that are – or might be – important in solution.
Formation and Thermal Rearrangement of Dimethyl Tricyclo[6.2.2.01,7]dodeca‐2,4,6,9,11‐pentaene‐9,10‐dicarboxylates
Authors: Fallahpour Reza‐Ali , Hansen Hans‐Jürgen
Published: December 2004

The high‐pressure reaction of 1‐methylazulenes 1 with excess of dimethyl acetylenedicarboxylate (ADM) in hexane at 30° and at pressures up to 7 kbar affords the tricyclic compounds 2 in reasonable‐to‐good yields (cf. Table 1). The crystalline compounds 2 decompose on melting into the starting materials and undergo rearrangement to the corresponding heptalene‐1,2‐dicarboxylates 6. The X‐ray crystal‐structure analyses of 2f and 2g (cf. Fig. 1) reveal the presence of a perfectly planar seven‐membered ring and comparably long C(1)–C(10) as well as C(1)–C(11) bonds (cf. Tables 2 and 3). The thermolysis of 2g in different solvents leads in aprotic media to the formation of the starting azulene 1g and, depending upon the polarity of the solvents, to varying amounts of the corresponding heptalene‐1,2‐dicarboxylate 6f (cf. Table 11). The formed amounts of 1g depends linearly on the ET values of the solvents (cf. Fig. 4). The same is valid for the thermolysis of 2g in protic media (cf. Table 10 and Fig.3). However, in these cases instead of the heptalene‐1,2‐dicarboxylate 6g, the corresponding (E)‐ and (Z)‐isomers of the 1‐(azulen‐1‐yl)ethene‐1,2‐dicarboxylates 7g are formed. The other tricyclic compounds 2 exhibit the same behavior on thermolysis in MeCN and BuOH (cf. Tables 8 and 9, resp.). The results show that the tricyclic compounds 2 undergo at temperatures up to 110° two competing reactions, namely heterolysis of the C(1)–C(10) bond, leading to the formation of heptalenes 6 in polar aprotic media, and the (E)‐ and (Z)‐ethene‐1,2‐dicarboxylates 7 in polar protic media, and concerted homolysis of the C(1)–C(10) and C(8)–C(9) bonds in the sense of a retro‐Diels‐Alder reaction in apolar media, yielding the starting azulenes and ADM, the amount of which decrease with increasing polarity of the solvent. The kinetic and activation parameters measured for 2g and the other tricyclic compounds 2 are collected in Tables 12–15. The tricyclic compounds 2a and 2b show in polar aprotic media (MeCN) a different behavior in that they form, instead of heptalenes, the corresponding 3,4‐dihydrocyclopent[cd]azulene‐1,2‐dicarboxylates 16a and 16b, respectively (Scheme 4). Experiments with [8‐2H]‐2a showed that these compounds are not formed via intramolecular H‐shifts (cf. Schemes 8 and 9).
Nucleic‐Acid Analogs with Restricted Conformational Flexibility in the Sugar‐Phosphate Backbone (‘Bicyclo‐DNA’). Part 5. Synthesis, Characterization, and Pairing Properties of Oligo‐α‐D‐(bicyclodeoxynucleotides) of the Bases Adenine and Thymine (α‐Bicyclo‐DNA)
Authors: Bolli Martin , Lubini Paolo , Leumann Christian
Published: December 2004

A conformational analysis of the (3′S,5′R)‐2′‐deoxy‐3′,5′‐ethano‐α‐D‐ribonucleosides (a‐D‐bicyclodeoxynucleosides) based on the X‐ray analysis of N4‐benzoyl‐α‐D‐(bicyclodeoxycytidine) 6 and on 1H‐NMR analysis of the α‐D‐bicyclodeoxynucleoside derivatives 1‐7 reveals a rigid sugar structure with the furanose units in the l′‐exo/2′‐endo conformation and the secondary OH groups on the carbocyclic ring in the pseudoequatorial orientation. Oligonucleotides consisting of α‐D‐bicyclothymidine and α‐D‐bicyclodeoxyadenosine were successfully synthesized from the corresponding nucleosides by phosphoramidite methodology on a DNA synthesizer. An evaluation of their pairing properties with complementary natural RNA and DNA by means of UV/melting curves and CD spectroscopy show the following characteristics: i) α‐bcd(A10) and α‐bcd(T10) (α = short form of α‐D)efficiently form complexes with complementary natural DNA and RNA. The stability of these hybrids is comparable or slightly lower as those with natural β‐d(A10) or β‐d(T10)( β = short form ofβ‐D). ii) The strand orientation in α‐bicyclo‐DNA/β‐DNA duplexes is parallel as was deduced from UV/melting curves of decamers with nonsymmetric base sequences. iii) CD Spectroscopy shows significant structural differences between α‐bicyclo‐DNA/β‐DNA duplexes compared to α‐DNA/β‐DNA duplexes. Furthermore, α‐bicyclo‐DNA is ca. 100‐fold more resistant to the enzyme snake‐venom phosphodiesterase with respect to β‐DNA and about equally resistant as α‐DNA.
Mechanism of Transfer of a Basic Drug across the Water/1,2‐Dichloroethane Interface: The case of quinidine
Authors: Reymond Frédéric , Girault Hubert H. , Steyaert Guillaume , Carrupt Pierre‐Alain , Testa Bernard
Published: December 2004

The electrochemical transfer of quinidine across the H2O/1,2‐dichloroethane interface was investigated by cyclic voltammetry, so as to determine its lipophilicity. The formal transfer potential was measured as a function of the pH of the aqueous phase. Both singly and doubly protonated quinidine cations can transfer across the interface, and their formal Gibbs free energies of transfer were observed to be 7.7 and 31.2 kJ mol−1, respectively. Between pH 0 and 3, only the doubly charged quinidine was present in the aqueous phase and was observed to transfer. Between pH 3 and 6, the transfer of both cations occurred. The proportion of doubly charged quinidine decreased progressively in this pH range and disappeared completely above pH 6. The overall process was analyzed using a thermodynamic model. The relationship between the various forms of quinidine in both phases and pH was established and found to be in good agreement with the experimental results. With this model, the acid‐base equilibrium constants in the organic phase could be calculated as pKa1o = 9.66 ± 0.21 and pKa2o = 14.20 ± 0.16 (the subscripts a1o and a2o refer to the first and second dissociation constants). This study illustrates how the partition of ionic species can be taken into account in the determination of lipophilicity and in the description of the passive transfer of organic drugs.
Synthesis and Tritium Labelling of 6β‐Amino‐4,5α‐epoxymorphinans and their 14‐hydroxy derivatives as potential affinity labelling probes with μ opioid agonist activity
Authors: Ötvös Ferenc , Tóth Géza , Lovas Sándor , Simon Csaba , Hosztafi Sándor
Published: December 2004

The synthesis of 6β‐(methylfumaramido) and 6β‐chloroacetamido derivatives 1b and 1c of 6β‐amino‐7,8‐ didehydromorphinan and the corresponding 14‐hydroxy derivatives 1e and 1f are described. The 7,8‐dihydro derivatives of these compounds were synthesized in inactive (2b,c,e,f) as well as in tritiated form (3b,c,e,f).
Synthesis of 6‐Substituted 1‐Deazapurine 2′‐Deoxyribonucleosides
Authors: Wenzel Thomas , Seela Frank
Published: December 2004

The synthesis of 6‐substituted 1‐deazapurine 2′‐deoxyribonucleosides is described. Glycosylation of the 1‐deazapurine (imidazo[4,5‐b]pyridine) anions with the α‐D‐halogenose 5 gives stereoselectively N7‐ and N9‐ regioisomers. 1H‐NMR NOE and 13C‐NMR spectroscopy are used for unambiguous assignment of isomers, and 15N‐NMR chemical shifts are correlated with σpara Hammett constants and point charges.
Säure‐Additionen an ‘Push‐Pull’‐Enine. Erste Beobachtung einer Umlagerung von 5‐Chloro‐5‐(dialkylamino)pentadienalen
Authors: Berger Daniel , Neuenschwander Markus
Published: December 2004

Reaction of ‘Push‐Pull’ Enynes with Acids. First Observation of a Rearrangement of 5‐Chloro‐5‐(dialkylamino)pentadienals

‘Push‐pull’‐enynes 7 react easily with HCl as well as with AcOH to give 5‐amino‐5‐chloropentadienals 8 and 5‐(acetoxy)‐5‐aminopentadienals 13 as well as the corresponding ketones. In view of a postulated rearrangement of compounds 8 and 13 (Scheme 2), both types of compounds have been treated with traces of acid. While no definite reaction is observed in case of 13, HCl‐addition products 8 easily and quantitatively rearrange to give 2H‐pyran‐2‐iminium chlorides 10 which are the postulated intermediates of the rearrangement 8→12 (Scheme 2).
A Novel Amination Reaction with Diphenyl Phosphorazidate: Synthesis of α‐amino‐acid derivatives
Authors: Villalgordo José M. , Linden Anthony , Heimgartner Heinz
Published: December 2004

The reaction of enolates of α‐unsubstituted carboxamides 3 with diphenyl phosphorazidate (DPPA) and di(tert‐butyl) dicarbonate (‘Boc anhydride’) in THF at −78° yielded 2‐{[(tert‐butoxy)carbonyl]amino}carboxamides 5 (Scheme 2) which are derivatives of α‐amino acids. In this reaction, DPPA acts as an electrophilic amination reagent. A reaction mechanism is proposed in Scheme 3.
Epoxyfocardin and Its Putative Biogenetic Precursor, Focardin, Bioactive, New‐Skeleton Diterpenoids of the Marine Ciliate Euplotes focardii from Antractica
Authors: Guella Graziano , Pietra Francesco , Dini Fernando
Published: December 2004

From the ciliate Euplotes focardii, collected from Ross Sea coastal waters, Antarctica, a new‐skeleton diterpenoid, epoxyfocardin, was isolated as a 85:15 mixture of hemiacetals 8a and 8b. The absolute configuration of 8a/8b was determined from Mosher's esters 11a/11b and 12a/12b. Focardin 9a/9b, most likely a biogenetic precursor of 8a/8b, was also isolated as a minor component. Focardin, and particularly epoxyfocardin, proved to be toxic towards representatives of ciliate communities from Antarctic, temperate, tropical, and equatorial environments, constituting the first example of ecologically relevant metabolites from ciliate species that inhabit polar ecosystems.
Synthesis of Coumarin Derivatives as Inhibitors of Platelet Aggregation
Authors: Chen Yeh‐Long , Wang Tai‐Chi , Lee Kuan‐Han , Tzeng Cherng‐Chyi , Chang Ya‐Ling , Teng Che‐Ming
Published: December 2004

In a search for the inhibitors of platelet aggregation, certain coumarin derivatives were synthesized and evaluated for antiplatelet activity against thrombin(Thr)‐, arachidonic acid(AA)‐, collagen(Col)‐, and platelet‐activating‐factor(PAF)‐induced aggregation in washed rabbit platelets. These compounds were synthesized from 4‐hydroxycoumarin (1) or naphthalen‐1‐ol via alkylation and Reformatsky‐type condensation (Schemes 1–3). Among them, 4‐[(2,3,4,5‐tetrahydro‐4‐methylidene‐5‐oxo‐2‐phenylfuran‐2‐yl)methoxy]‐2H‐1‐benzopyran‐2‐one (6b) showed potent antiplatelet effects on AA‐ and PAF‐induced aggregation with IC50 values of 8.21 and 103.67 m̈M, respectively (see Tables 1 and 2). The antiplatelet potency of 6b against PAF‐induced aggregation could be further improved by introducing a proper substituent at the 2‐phenyl group of the lactone ring.
First Fullerene[60]‐Containing Thermotropic Liquid Crystal. Preliminary Communication
Authors: Chuard Thierry , Deschenaux Robert
Published: December 2004

The synthesis and liquid‐crystalline and thermal properties of a fullerene[60] functionalized by a framework containing two cholesterol derivatives through a methanofullerene structure are reported. The targeted fullerene derivative showed high thermal stability.
Dendrophanes: Novel Steroid‐Recognizing Dendritic Receptors. Preliminary Communication
Authors: Wallimann Peter , Seiler Paul , Diederich François
Published: December 2004

The H2O‐soluble dendritic cyclophanes (dendrophanes) 3–5 of first to third generation with molecular weights up to nearly 20 kD were synthesized, purified, and characterized. Cyclophane 2, which served as the initiator core (generation zero), was prepared from tetrabromocyclophane 10 in a four‐step sequence which involved as the first transformation a high‐yielding, four‐fold Pd(0)‐catalyzed Suzuki cross‐coupling reaction with 4‐(benzyloxy)‐phenyl‐boronic acid to give 18. The X‐ray crystal‐structure analysis of tetrabromocyclophane 10 displayed an open, nearly rectangular box with opposite aromatic walls being 8.3 and 11.4 Å apart and of suitable size for the incorporation of steroidal substrates. 1H‐NMR Binding titrations in borate‐buffered D2O/CD3OD 1:1 showed that cyclophane‐tetracarboxylate 2 forms 1:1 inclusion complexes with steroids (Table 2). Complexation was found to be enthalpically driven with higher binding affinities measured for the more apolar substrates. 1H‐NMR Titrations in the same solvent also provided clear evidence for core‐selective complexation of testosterone (21) by the dendrophanes 3 (1st), 4 (2nd), and 5 (3rd generation) carrying up to 108 carboxylate surface groups. The stability of the corresponding 1:1 complexes was hardly affected by the size of the dendritic shell, although some generation‐dependent conformational changes in the receptor cavity seemed to take place. Remarkably, host‐guest exchange kinetics in all recognition processes were fast on the 1H‐NMR time scale.
Synthesis and Luminescence of Novel EuIII Complexing Agents and Labels with 4‐(Phenylethynyl)pyridine Subunits
Authors: Takalo Harri , Hemmilä Ilkka , Sutela Timo , Latva Martti
Published: December 2004

The synthesis of novel 4‐(phenylethynyl)pyridine subunits containing H2O‐soluble complexing agents and their luminescence with EuIII ions are reported. Ligands with high luminescence intensities as well as quantum yields were obtained. Also the prepared labeling reagents as antibody conjugates gave the highest quantum and luminescence yields reported for H2O‐soluble EuIII labels.
1,5‐Dipolare Elektrocyclisierung von Acyl‐substituierten ‘Thiocarbonyl‐yliden’ zu 1,3‐Oxathiolen
Authors: Kägi Martin , Linden Anthony , Heimgartner Heinz , Mlostoń Grzegorz
Published: December 2004

1,5‐Dipolar Electrocyclization of Acyl‐Substituted ‘Thiocarbonyl‐ylides’ to 1,3‐Oxathioles

The reaction of α‐diazoketones 15a, b with 4,4‐disubstituted 1,3‐thiazole‐5(4H)‐thiones 6 (Scheme 3), adamantanethione (17), 2,2,4,4‐tetramethyl‐3‐thioxocyclobutanone (19; Scheme 4), and thiobenzophenone (22; Scheme 5), respectively, at 50–90° gave the corresponding 1,3‐oxathiole derivatives as the sole products in high yields. This reaction opens a convenient access to this type of five‐membered heterocycles. The structures of three of the products, namely 16c, 16f, and 20b, were established by X‐ray crystallography. The key‐step of the proposed reaction mechanism is a 1,5‐dipolar electrocyclization of an acyl‐substituted ‘thiocarbonyl‐ylide’ (cf. Scheme 6). The analogous reaction of 15a, b with 9H‐xanthen‐9‐thione (24a) and 9H‐thioxanthen‐9‐thione (24b) yielded α,β‐unsaturated ketones of type 25 (Scheme 5). The structures of 25a and 25c were also established by X‐ray crystallography. The formation of 25 proceeds via a 1,3‐dipolar electrocyclization to a thiirane intermediate (Scheme 6) and desulfurization. From the reaction of 15a with 24b in THF at 50°, the intermediate 26 (Scheme 5) was isolated. In the crude mixtures of the reactions of 15a with 17 and 19, a minor product containing a CHO group was observed by IR and NMR spectroscopy. In the case of 19, this side product could be isolated and was characterized by X‐ray crystallography to be 21 (Scheme 4). It was shown that 21 is formed – in relatively low yield – from 20a. Formally, the transformation is an oxidative cleavage of the CC bond, but the reaction mechanism is still not known.
Chemistry and the Origin of Life
Authors: Eschenmoser Albert , Volkan Kisakürek M.
Published: December 2004

The natural genesis of life on Earth is a hypothesis of evolutionary science; it is the task of synthetic organic chemistry to test this hypothesis experimentally. The aim of an experimental aetiological chemistry is not primarily to delineate the pathways along which our (‘natural’) life on Earth could have originated, but to provide decisive experimental evidence, through the realization of model systems (‘artificial chemical life’), that life can arise as a result of the organization of organic matter.
A Reinvestigation of the Oxidative Rearrangement of Yohimbane‐Type Alkaloids. Part B. Formation of Oxindol (= 1,3‐Dihydro‐2H‐indol‐2‐one) Derivatives
Authors: Stahl Reto , Borschberg Hans‐Jürg , Acklin Pierre
Published: December 2004

The methanolysis of the epimeric 7‐chloro‐7H‐yohimbine derivatives 2 and 3 was reinvestigated. In case of the 7α‐epimer 2, the reaction was uneventful and conformed with earlier observations, i.e., under sufficiently mild conditions, only the imino ether 4 (= imino ether A) was produced. Under the same conditions, the less reactive β‐isomer 3 furnished a mixture of both imino ethers 4 and 5, accompanied by the elimination product 11, and by equal amounts of yohimbine (1) and 3,4,5,6‐tetradehydroyohimbine (12), which are believed to arise through a disproportionation process of the putative intermediate 5,6‐didehydroyhimbine (23). The nature of this divergent reactivity and of the ready equilibration of 4 and 5 was investigated by means of extensive force‐field and semi‐empirical calculations (AM1 and PM3) of various conformers of the compounds 2–5 and of some possible reaction intermediates.
Intramolecular Vinyl Radical Cyclization Reactions of cyclohexadienes derived from sequential additions to (arene)(tricarbonyl)chromium complexes. Preliminary communication
Authors: Beruben Dov , Kündig E. Peter
Published: December 2004

Cyclohexa‐1,3‐dienes 7–10 with a 1,5,6‐substitution pattern were prepared in a one‐pot reaction sequence by sequential addition of MeLi and propargyl bromides to the tricarbonylchromium complex 1a. These products were subjected to radical cyclization procedures. Vinyl radical generation by Bu3Sn addition to the propargyl group in 7–10 was followed by regio‐ and diastereoselective intramolecular ring closure. Two different 5‐exo‐trig cyclizations are possible via different vinyl radical intermediates and cyclization to one or the other of the termini of the cyclohexadiene moiety. Internal alkynes reacted to yield exclusively the cis‐fused hexahydroindene products 12–14, whereas the terminal alkyne yielded bicyclo[3.2.1]octenes 11 as sole products.
Determination of the Configuration of Wine Lactone
Authors: Guth Helmut
Published: December 2004

The intense sweet and coconut‐like smelling odorant 1, named ‘wine lactone’, was isolated from different wine varieties. The chemical structure of this compound, which has not yet been detected in wine or a food, was identified by high‐resolution mass spectrometry (HR‐MS) as 3a,4,5,7a‐tetrahydro‐3,6‐dimethylbenzofuran‐2(3H)‐one. For the evaluation of the configuration of wine lactone, stereochemically controlled syntheses were developed. All eight isomers were characterized by NMR, MS, IR, and CD measurements. The configuration of ‘wine lactone’ was in agreement with synthesized (3S,3aS,7aR)‐enantiomer (1a) on the basis of enantioselective GC. For this isomer, the lowest odor threshold (0.02 pg/1 air) was detected.
The Addition of tert‐Butyl (Me3Ċ) and (tert‐Butoxy)carbonylmethyl (Me3CO2CĊH2) radicals to alkynes in solution studied by ESR spectroscopy
Authors: Rubin Herbert , Fischer Hanns
Published: December 2004

Absolute rate constants and their temperature dependence are determined by time‐resolved electron spin resonance for the addition of Me3Ċ to 20 and of Me3CO2CĊH2 to six mono‐ and disubstituted alkynes in solution. For Me3Ċ the rate constants show polar alkyne‐substituent effects which are, however, weaker than for the corresponding alkenes. For Me3CO2ĊH2, the rate constants do not vary strongly with alkyne substitution and probably increase with increasing reaction exothermicity. Both radicals react generally slower with alkynes than with alkenes which is discussed in terms of the state correlations. Several vinyl‐type radical adducts of Me3Ċ to alkenes are characterized by electron spin resonance, and their spectral data indicate linear or bent configurations of the radical carbon depending on the substitution.
Ionization and Partitioning Profiles of Zwitterions: The case of the anti‐inflammatory drug azapropazone
Authors: Caron Giulia , Pagliara Alessandra , Gaillard Patrick , Carrupt Pierre‐Alain , Testa Bernard
Published: December 2004

Azapropazone (1) is a non‐steroidal anti‐inflammatory drug (NSAID) whose chemical structure is markedly different from that of other agents in this class and challenges our understanding of structure‐activity and structure‐permeation relationships. Using a variety of experimental and computational techniques, we studied 1 for its molecular structure in the gas phase and non‐protic polar solvents, protonation/deprotonation equilibra, tautomerism, and pH‐lipophilicity profiles (octan‐1‐ol/H2O and dodecane/H2O). Other NSAIDs and model compounds were also examined for comparison. Due to its very low acidic pKa1, 1 exists in the physiological pH range as a zwitterion and as an anion. Some pharmacological implications of these findings are discussed.
The Degradation Mechanism of an Oral Cephalosporin: Cefaclor
Authors: Vilanova Bartolomê , Donoso Josefa , Muñoz Francisco , García‐Blanco Francisco
Published: December 2004

The degradation of cefaclor (1), an oral cephalosporin antibiotic, was studied at 37° in a neutral aqueous medium by HPLC and 1H‐NMR. Under these conditions, 1 underwent intramolecular aminolysis by the 7‐side‐chain NH2 group on the β‐lactam moiety to give a piperazine‐2,5‐dione. The most prominent peak in the HPLC profile of a degradation solution from 1 was isolated by prep. HPLC. Mechanistically, the formation of this degradation product cis‐11 from 1 involves the contraction from a six‐membered cephem ring to a five‐membered ring, which presumably takes place via a common episulfonium ion intermediate 9 (see Scheme). Loss of the Cl‐atom from 3‐chloro‐3‐cephem is a general reaction subsequent to β‐lactam ring opening.
Chiral Diselenides from Benzylamines: Catalysts in the Diethylzinc Addition to Aldehydes
Authors: Wirth Thomas , Kulicke Klaus J. , Fragale Gianfranco
Published: December 2004

A series of new chiral diselenides with a N‐atom in the side chain was prepared by a short synthetic sequence (Scheme 1). Only 1 mol‐% of these diselenides catalyzed very effectively the diethylzinc addition to various aromatic and α,β‐unsaturated aldehydes yielding the secondary alcohols in up to 98% ee (Scheme 2 and Tables 1 and 2). An asymmetric amplification was observed with these catalysts. Detailed NMR studies were performed to characterize the catalytically active species.
Lipid Masking and Reactivation of Angiotensin Analogues
Authors: Maletínskâ Lenka , Neugebauer Witold , Parê Marie‐Christine , Pêrodin Jacqueline , Pham Dung , Escher Emanuel
Published: December 2004

Studies on post‐angioplastic restenosis have shown the implication of angiotensin II (Ang) as a myoproliferative mediator. The antiproliferative efficacy of non‐peptide Ang antagonists on the rat carotid model is of 50%, whereas a continuously infused peptide antagonist at low doses totally blocks neointimal growth. To explore the feasibility of depot forms of Ang that may be introduced during angioplasty and thus prevent restenois, lipid‐masked Ang analogues of the following general structure were prepared: [Xxx°, Yyy1]Ang with Xxx = decanoyl or palmitoyl and Yyy = Ser, Cys, Asp, β‐lactoyl, 3‐mercaptopropanoyl or succinyl. All fatty acylated peptides [Xxx°, Yyy1]Ang were practically inactive, and O‐ or S‐esterified Ser and Cys peptides underwent intramolecular transcylation giving inactive Nx‐acylated peptides. O‐Acylated [β‐mercaptopropanoyl1]Ang were easily hydrolyzed into their biologically active[Yyy1]Ang forms, either by mild saponification or by lipase activity.
A Formal Total Synthesis of (+)‐Methyl Trachyloban‐18‐oate and (+)‐Methyl 16‐Oxo‐17‐norkauran‐18‐oate: Regio‐ and Diastereoselective Preparation of Methyl (13S)‐13‐Hydroxyisoatisiren‐18‐oate from (−)‐Abietic Acid
Authors: Berettoni Marco , De Chiara Giovanna , Iacoangeli Tommaso , Lo Surdo Paola , Bettolo Rinaldo Marini , Di Mirabello Lorenzo Montagnini , Nicolini Luca , Scarpelli Rita
Published: December 2004

A novel preparation of methyl (13S)‐13‐hydroxyisoatisiren‐18‐oate (4), a key‐intermediate in a synthesis of (+)‐methyl trachyloban‐18‐oate ((+)‐1), from (−)‐abietic acid, is described. Since (−)‐1 has been previously converted into (−)‐methyl 16‐oxo‐17‐norkauran‐18‐oate ((−)‐16), our preparation of 4 constitutes also a formal total synthesis, from (−)‐abietic acid, of (+)‐16. Key steps in this approach were the allene photoaddition to podocarp‐8(14)‐en‐13‐one (5) and the conversion of the endo‐toluene‐4‐sulfonate 11 into the exo‐benzoate 12b.
Synthesis of 1,2,5‐Thiadiazepine Derivatives by Ring Enlargement of 1,2‐Thiazetidin‐3‐one 1,1‐Dioxides with 3‐Amino‐2H‐azirines
Authors: Mihova Tonya R. , Linden Anthony , Heimgartner Heinz
Published: December 2004

At 0° in MeCN, 2,2‐disubstituted 3‐amino‐2H‐azirines 1 and 4,4‐disubstituted 1,2‐thiazetidin‐3‐one 1,1‐dioxides 7 react smoothly to give 1,2,5‐thiadiazepin‐6‐one 1,1‐dioxides of type 8 (Scheme 2). The reaction mechanism of this regiospecific ring enlargement to seven‐membered heterocycles follows previously described pathways. The structures of 7a and 8b were established by X‐ray crystallography (see Figs. 1 and 2).
From Inactive Nortopsentin D, a Novel Bis(indole) Alkaloid Isolated from the Axinellid Sponge Dragmacidon sp. from Deep Waters South of New Caledonia, to a Strongly Cytotoxic Derivative
Authors: Mancini Ines , Guella Graziano , Pietra Francesco , Debitus Cécile , Waikedre Jean
Published: December 2004

Nortopsentin D (5), a bis(indole) alkaloid unique for bearing a 2‐amino‐methylimidazole appendage at the central 1H‐imidazol‐5(4H)‐one nucleus, was isolated in abundance, besides the putative biogenetic precursor 6 of its appendage, from the deep‐water axinellid sponge Dragmacidon sp. Structural elucidation of 5 by NMR and MS methods heavily relied on its N‐methyl derivatives 8–11. Unusually for topsentin‐type structures, natural 5 and semisynthetic methyl derivatives 8 and 10 proved inactive on KB tumoural cells, while introduction of the last three methyl groups, amazingly led to highly cytotoxic 11.
Synthesis of Enantiomerically Pure Carbohydrate‐Derived Annulated Cyclopentadienes and Ferrocenes
Authors: Li Zhi , Vasella Andrea
Published: December 2004

The cyclopentadienes 3a/b/c, 8b/c, 12a/b/d, and 16a/b/d were prepared as mixtures of regioisomers from the D‐mannitol‐derivatives 1,6,10, and 14 and transformed into the ferrocenes 17, 18, and 19 (73%; 38:17:45), 23, 24, and 25 (70%; 6:42 :52), 26 (31%), and 27 (27%), respectively. Deprotection of 17–19 with HCl/MeOH gave the H2O‐soluble ferrocenes 20–22; chloromercuration and iodination of 17 via 29 led to the C2‐symmetric diiodo‐ferrocene 30. The mono(chloromercurio) derivative 28, obtained as a by‐product, was also transformed into 29. The structure of the ferrocenes 18 and 19, and of the bis(chloromercurio)ferrocene 29 has been established by X‐ray analysis. The starting cyclopentadienes 3 were obtained in 50% yield from 1 by dialkylation of CpNa, followed by thermolysis of the spiro‐annulated 2. Similarly, dimesylate 6 (from 4) gave the spiro‐annulated diene 7 and the annulated dienes 8 in about equal amounts; thermolysis transformed 7 into 8 (62%). The dienes 12 were prepared in 15% yield from the ditriflate 10 via 11, the dimesylate 9 proving insufficiently reactive, and the dienes 16 (49%) from 14 via 15.
Multiple Adducts of C60 by Tether‐Directed Remote Functionalization and synthesis of soluble derivatives of new carbon allotropes Cn(60+5)
Authors: Isaacs Lyle , Diederich François , Haldimann Richard F.
Published: December 2004

A comprehensive series of multiple adducts of C60 was prepared by tether‐directed remote functionalization. When the tether‐reactive‐group conjugates 2 and 10 were attached to methano[60]fullerenecarboxylic acid ( = cyclopropafullerene‐C60‐Ih‐carboxylic acid) and C60, respectively, the e‐bis‐adducts 4 and 9 (Schemes 1 and 2) were obtained with complete regioselectivity as predicted by semi‐empirical PM3 calculations (Fig. 2). Attachment of the anchor‐tether‐reactive‐group conjugate 13 to C60 by Bingel reaction, followed by double intramolecular Diels‐Alder cycloaddition afforded the tris‐adduct 12 (Scheme 3). Starting from 12, a series of selective e‐additions led to the tetrakis‐adducts 16 and 19 (Scheme 4), pentakis‐adducts 20–23 (Scheme 5), and, ultimately, to hexakis‐adducts 24 and 25 (Scheme 6), and 29 and 30 (Scheme 7) with a pseudo‐octahedral addition pattern on the fullerene core. Oxidative cyclization of diethynylmethanofullerene 30 under Eglinton‐Glaser conditions afforded the trimeric and tetrameric acetylenic macrocycles 26, with three, and 27, with four appended C60 moieties, respectively (Scheme 8). These multinanometer‐sized compounds are the first soluble derivatives of C195 and C260, two members of a new class of fullerene‐acetylene hybrid C‐allotropes with the general formula Cn(60 + 5). The matrix‐assisted laser‐desorption time‐of‐flight mass spectra of 26 and 27 showed a remarkable fragmentation; the sequential loss of fullerene spheres led to the formation of ions corresponding to mono‐fullerene adducts of the cyclocarbons cyclo‐C15 and cyclo‐C20 (Fig. 4). Large solvent effects were observed in the Bingel addition of 2‐bromomalonates to higher adducts of C60, with the use of polar solvents enhancing the reaction rate without loss of regioselectivity. Experimental evidence for the enhanced reactivity of eface over eedge bonds was obtained, which had previously been predicted in computational studies. The correlated series of mono‐ to hexakis‐adducts of C60 allowed identification of the changes in reactivity and physical properties that occur, when the conjugated π‐electron chromophore of the fullerene is reduced as a result of increasing functionalization; this analysis is the subject of the directly following paper.
Steroidal, Aldosterone Antagonists: Increased selectivity of 9α,11‐epoxy derivatives
Authors: Grob Jürgen , Boillaz Michel , Schmidlin Julius , Wehrli Hansuli , Wieland Peter , Fuhrer Hermann , Rihs Grety , Joss Urs , Gasparo Marc De , Haenni Henry , Ramjoué Hans Peter , Whitebread Steven E. , Kalvoda Jaroslav
Published: December 2004

In the search for aldosterone antagonists with an optimal activity profile, twelve 9α, 11‐epoxy‐steroids were prepared and compared with their 9α, 11α ‐unsubstituted analogues in terms of steroid receptor binding in vitro and electrolyte excretion in vivo. Substitution of the parent structures by an epoxy group at positions 9α, 11 resulted in marginal effects on mineralocorticoid receptor binding and electrolyte excretion, but greatly reduced androgen and gestagen receptor binding. This finding is reflected in the largely lacking unwanted anti‐androgenic and gestagenic side effects in animal models of the three most interesting 9α, 11 ‐epoxy‐spirolactones 4(CGP 33033), 18(CGP 29245), and 25 (CGP 30083).
Study of the Alkaline Hydrolysis of the Azetidin‐2‐one Ring by ab initio Methods: Influence of the solvent
Authors: Frau Juan , Donoso Josefa , Muñoz Francisco , Vilanova Bartolomé , García‐Blanco Francisco
Published: December 2004

A comprehensive study of the alkaline hydrolysis of the β‐lactam ring of azetidin‐2‐one was carried out using ab initio molecular‐orbital calculations at the RHF/6‐31 + G* level. The influence of the solvent on this reaction was investigated by using the reaction field method (SCRF); the solvent was found to suppress the interference of some gas‐phase reactions and allow the presence of a transition state to be detected as the nucleophile approaches the β‐lactam ring. The transition state corresponds to a structure where the OH− group lies at a distance of 1.927 Å from the CO group of the β‐lactam ring and exhibits a potential barrier of 13.6 kcal/mol.
Selective Synthesis of Polyamine Derivatives: Efficient derivatization of the secondary amino group of N‐monosubstituted 1,3‐diamines
Authors: Jentgens Christian , Hofmann Richard , Guggisberg Armin , Bienz Stefan , Hesse Manfred
Published: December 2004

N‐Monosubstituted 1,3‐diamines were selectively functionalized at the secondary N‐atom via 2‐Ph‐substituted hexahydropyrimidine intermediates. Reaction of the diamines with benzaldehyde, followed by treatment with an electrophile and hydrolysis, provided the desired products with excellent selectivity and in high yields. N4,N9‐bis[3‐phenylprop‐2‐enoyl]spermine (4a), which was further converted to N1,N1 2‐bis[3‐phenylprop‐2‐enoyl]spermine (15) by a transamidation reaction, was prepared by this way in 82% yield from spermine (1). Compound 4a was alternatively synthesized in 83% yield, equally from 1, by a sequence involving intermediary protection of the terminal amino groups.
Structure‐Activity Relations for Imidazo‐pyridine‐Type Inhibitors of β‐D‐Glucosidases
Authors: Granier Thierry , Panday Narendra , Vasella Andrea
Published: December 2004

The triazole 7 and the known gluco‐ and manno‐configurated imidazoles 10 and 11 have been prepared by annulation of the azole ring to the aldonothiolactam 14 in a Hg(OAc)2‐promoted reaction with either hydrazine‐carbaldehyde or aminoacetaldehyde dimethyl acetal. Depending upon the reaction conditions, the synthesis of the imidazoles yielded mostly the gluco‐imidazole 19 or a mixture of the gluco/manno epimers 19/20. In contrast to the triazole 4, the isomeric triazole 7 proved a good inhibitor of retaining β‐glucosidases from sweet almonds and from Caldocellum saccharolyticum. This observation and the qualitative correlation between basicity and inhibitory power of the tetrahydropyridoazoles provide further evidence for the hypothesis of the ‘lateral protonation’ of glycosides by (some) retaining β‐glucosidases.
Oligosaccharide Analogues of Polysaccharides. Part 12. Synthesis of ‘acetyleno‐saccharide’‐derived cyclodextrin analogues
Authors: Bürli Roland , Vasella Andrea
Published: December 2004

‘Acetyleno‐oligosaccharides’ in which two terminal ethynyl substituents enclose an angle (significantly) below 180° are building blocks for the preparation of cyclodextrin analogues. This is illustrated by the preparation of a cyclotrimer and a cyclotetramer; the C3‐symmetrical cyclotrimer 18 (Scheme 1) was synthesized in 13 steps (7.7%) and the C4‐symmetrical cyclotetramer 51 (Scheme 3) in 14 steps (4.3%) from the known dialkyne 21. The solubilities of 18 and 51 in H2O were determined by gravimetry; a saturated solution is 130 mM in the trimer 18 and 12.8 mM in the tetramer 51. The dependence of the optical rotation of 18 and 51 in H2O on the concentration, and the concentration dependence of the 1H‐NMR chemical shift of the signals of the 1CH groups of 51 (D2O) suggest that there is no significant self‐association of 18 and 51.
Selective Monoderivatization of Propane‐1,3‐diamine with Acid Chlorides: ‘Hexahydropyrimidine method’ vs. statistic methods
Authors: Jentgens Christian , Bienz Stefan , Hesse Manfred
Published: December 2004

The selective N‐monoderivatization of propane‐1,3‐diamine (5) with carbonyl and sulfonyl chlorides via2‐phenylhexahydropyrimidine (6) was compared with the direct statistic monoderivatization. It was found that, under optimized conditions, both methods are competitive to one another, depending, however, strongly on the reactivity of the eleclrophile used. The ‘hexahydropyrimidine method’ is more reliable with respect to yields, which are moderate but invariably between 54 and 69%, whereas the ‘statistic method’ leads in certain cases to exceptionally high yields (up to 96%), in others, however, almost none.
Synthesis via a Carbohydrate‐Derived Münchnone of Pyrrolopyridines (Indolizines) and imidazopyridines, and their evaluation as inhibitors of β‐D‐glucosidases
Authors: Granier Thierry , Gaiser Florian , Hintermann Lukas , Vasella Andrea
Published: December 2004

In the presence of activating agents, the N‐acylglycine 8 reacts with electrophilic alkynes via the münchnone9 to the pyrrolopyridines (= indolizines) 10, 18, and 19 (Scheme 1 ), Depending on the nature of the activating agent and the reaction temperature, the formation of the pyrroles was accompanied by partial epimerization to the manna‐configurated epimers 16 and 17. The gluco‐configurated pyrrolopyridine 10 was deprotected to 12. Silylation of 12, followed by reduction and desilylation, gave the hexol 15. Cycloaddition of 9 to 4‐toluenesulfonyl cyanide yielded 53% of the imidazole 23, while cycloaddition to phenyl cyanate gave the phenoxyimidazole 28 in low yields only (Scheme 2). As expected, the deprotected pyrroles 12, 15, 20, and 21 are weak inhibitors of retaining β‐glucosidases, while the deprotected imidazole 24 derived from 23 proved a good inhibitor of sweet‐almond β‐glucosidases and a powerful inhibitor of Caldocellum saccharolyticum β‐glucosidase.