bluuebunny/crossref_metadata_2025 huggingface dataset:
Macrocyclic Tetraethynylethene Molecular Scaffolding: Perethynylated aromatic dodecadehydro[18]annulenes, antiaromatic octadehydro[12]annulenes, and expanded radialenes
Authors: Anthony John , Boldi Armen M. , Boudon Corinne , Gisselbrecht Jean‐Paul , Gross Maurice , Seiler Paul , Knobler Carolyn B. , Diederich François
Published: December 2004

Tetraethynylethene (3,4‐diethynylhex‐3‐ene‐1,5‐diyne) molecular scaffolding provided access to novel macrocyclic nanometer‐sized C‐rich molecules with unusual structural and electronic properties. Starting from cis‐bis‐deprotected cis‐bis(trialkylsilyl)protected tetraethynylethenes, the per(silylethynyl)ated octadehydro[12]annulenes 1 and 2 and the corresponding dodecadehydro[18]annulenes 4 and 5 were prepared by oxidative Hay coupling. X‐Ray crystal‐structure analyses of (i‐Pr)3Si‐protected 2 and Me3Si‐protected 4 showed that both annulene perimeters are perfectly planar. Electronic absorption spectral comparisons provided strong evidence that the macro rings in the deep‐purple‐colored 1 and 2 are antiaromatic (4n π‐electrons), whereas those in yellow 4 and 5 are aromatic ((4n + 2) π‐electrons). Although unstable in solution, the antiaromatic compound 2 gave high‐melting crystals in which the individual octadehydro[12]annulene chromophores are isolated and stabilized in a matrix‐type environment formed by the bulky (i‐Pr)3Si groups. Electrochemical studies demonstrated that the antiaromatic octadehydro[12]annulene 2 undergoes two stepwise one‐electron reductions more readily that the aromatic chromophore 5. This redox behavior is best explained by the formation of an aromatic (4n + 2) π‐electron dianion from 2, whereas 5 loses its aromaticity upon reduction. The Me3Si derivative 4 was deprotected with borax in MeOH/THF to give the highly unstable hexaethynyl‐dodecadehydro[18]annulene 6, a C30H6 isomer and macrocyclic precursor to a two‐dimensional all‐C‐network. Deprotection of 2 did not give isolable amounts of tetraethynyl‐octadehydro[12]annulene 3 due to the extreme instability of the latter. Starting from dimeric and trimeric acyclic tetraethynylethene oligomers, a series of expanded radialenes were obtained. They possess large C‐cores with silylethynyl‐protected peripheral valences and can be viewed as persilylated C40 (7), C50 (8), and C60 (9) isomers. These expanded C‐sheets are high‐melting, highly stable, soluble materials which were readily characterized by laser‐desorption time‐of‐flight (LD‐TOF) mass spectrometry. Due to inefficient macrocyclic cross‐conjugation and/or non‐planarity, the extent of π‐electron delocalization in 7–9 is limited to the longest linearly conjugated π‐electron fragment. In agreement with these properties, all three expanded radialenes exhibited similar redox behavior; they are difficult to oxidize but undergo several reversible one‐electron reductions in similar potential ranges. Presumably, the reduced π‐electron delocalization is also at the origin of the particularly high stability of 7–9.
Über die Biosynthese von γ‐Dodecanolacton in reifenden Früchten: Aroma‐Komponenten der Erdbeere (Fragaria ananassa) und des Pfirsichs (Prunus persica)
Authors: Schöttler Michael , Boland Wilhelm
Published: December 2004

On the Biosynthesis of γ‐Dodecanolactone in Ripening Fruits: Flavor Constituents from Strawberries (Fragaria ananassa) and Peaches (Prunus persica)

Administration of deuterium‐labelled 9,10‐expoxy[8,8‐2H2]heptadecanoic acid 8a/b and 9,10‐dihydroxy‐[8,8‐2H2]methylheptadecanoate 9 as lower analogues of oleic acid 1 to ripening fruits of strawberries (Fragaria ananassa) and peaches (Prunus persica) results in the emission of labelled γ‐undecanolactone (5) as the lower analog of γ‐dodecanolactone (2). The transformation proceeds with loss of a single D‐atom from C(8) of the precursors. Early precursors, like the C17‐epoxy‐acids 8a/b yield (4R)‐γ‐undecanolactone (5) of high enantiomeric purity, while later intermediates results in (4R)‐γ‐undecanolactone (5) of low purity. The data support a biosynthetic sequence involving the consecutive action of an epoxide hydrolase and β‐oxidation to generate the correct chain length of the lactone percursor. The final steps proceed via cyclization of the 3,4‐dihydroxyundecanoic acid 13 to the 3‐hydroxy‐γ‐undecanolactone 14. Elimination of H2O and reduction of the intermediate γ‐undec‐2‐enolactone 15 terminate the biosynthesis of 5. The sequence is representative for the biosynthesis of naturally occurring γ‐dodecanolactone (2).
Optisch aktive 3‐Amino‐2H‐azirine als Bausteine für enantiomerenreine α,α‐disubstituierte α‐Aminosäuren: Synthese des α‐Methylphenylalanin‐Synthons and Einbau in Modell‐Peptide
Authors: Bucher Christoph B. , Linden Anthony , Heimgartner Heinz
Published: December 2004

Optically Active 3‐Amino‐2H‐azirines as Synthons for Enantiomerically Pure αα‐Disubstituted α‐Amino Acids: Synthesis of the α‐Methylphenylalanine Synthons and Some Model Peptides

The synthesis of a novel 2‐benzyl‐2‐methyl‐3‐amino‐2H‐azirine derivative with a chiral amino group is described. Chromatographic separation of the diastereoisomer mixture yielded the pure diastereoisomers 9a and 9b (Scheme 4) which are the D‐ and L‐2‐methylphenylalanine ((α‐Me)Phe) synthons, respectively. The reaction of 9a and 9b with thiobenzoic acid and with Z‐leucine yielded the monothiodiamides 10a and 10b (Scheme 5) and the dipeptide derivatives 11a and 11b (Scheme 6), respectively. Methanolysis of 11b yielded 12b. The absolute configuration of 10a was established by X‐ray crystallography. The absolute configuration of (α‐Me)Phe in 12b has been deduced from the known configuration of L‐leucine.
Enantioselektive Synthese von Allyl‐, Propargyl‐ und 4‐En‐2‐inyl‐aminen durch 1,2‐Addition von Organocer‐Reagenzien an chirale Aldimine
Authors: Enders Dieter , Schankat Jürgen
Published: December 2004

Enantioselective Synthesis of Allyl‐, Propargyl‐, and 4‐En‐2‐ynyl‐amines via 1,2‐Addition of Organocerium Reagents to Chiral Aldehyde Imines

(E)‐ and (Z)‐Allyl‐, propargyl‐, and 4‐en‐2‐ynyl‐amines 5 and 14, useful bifunctional building blocks and of pharmaceutical interest, are synthesized in high enantiomeric purity (e.e. ≥ 97%). Key step is the diastereoselective 1,2‐addition (d.e. 86 to ≥ 98%) of organocerium reagents to chiral α,β‐unsaturated aldehyde imines 3 or 8 to produce adduct amines 4 and 9 (Schemes 1 and 4, resp.). The propargylamine 9 is a substrate for Pd‐catalyzed coupling with alkenyl halides to produce the enynylamine 11a and the thienyl‐substituted alkynylamine 11b. The chiral auxiliary (S,S)‐2 is removed from 4 and 11 in 3 steps affording the title compounds 5 and 14. Diastereoisomer enrichment of the hydrochloride of 6 by crystallization is possible.
Bildung von 1,2,4‐Trithiolanen in Dreikomponenten‐Gemischen aus Phenyl‐azid, aromatischen Thioketonen und 2,2,4,4‐Tetramethylcyclobutanthionen: Eine Schwefel‐Transfer‐Reaktion unter Bildung von ‘Thiocarbonylthiolaten’ ((Alkylidensulfonio)thiolaten) als reaktive Zwischenstufen
Authors: Mlostoń Grzegorz , Heimgartner Heinz
Published: December 2004

Formation of 1,2,4‐Trithiolanes in Three‐Component Reactions of Phenyl Azide, Aromatic Thiones, and 2,2,4,4‐Tetramethylcyclobutanethiones: A Sulfur‐Transfer Reaction to ‘Thiocarbonyl‐thiolates’ ((Alkylidenesulfonio)‐thiolates) as Reactive Intermediates

The reaction of PhN3 and aromatic thioketones 18 (two‐component reaction) at 80° yields only the corresponding imines 22, S, and N2. Under similar conditions, in the presence of sterically crowded 2,2,4,4‐tetramethyl‐cyclobutanethiones 19 (three‐component reaction), 1,2,4‐trithiolanes of type 20 are formed in good yields in addition to imines 22 (Scheme 4). In case of 19a and 19c (X = CO, CS), the symmetrical trithiolanes 21a and 21b, respectively, are also isolated. With 4,4‐dimethyl‐2‐phenyl‐1,3‐thiazole‐5(4H)‐thione (24) instead of aromatic thioketone 18, imine 25, trithiolane 21a, and 1,4,2‐dithiazolidine 26 are formed (Scheme 5). A reaction mechanism for the formation of 1,2,4‐trithiolanes 20 and 21, including an S‐transfer to generate ‘thiocarbonyl‐thiolates’ 2b and/or 2c and 1,3‐dipolar cycloaddition with a thioketone, is proposed in Scheme 7.
Novel open‐chain and cyclic conformationally constrained (R)‐ and (S)‐α,α‐disubstituted tyrosine analogues
Authors: Obrecht Daniel , Lehmann Christian , Ruffieux Ruth , Schönholzer Peter , Müller Klaus
Published: December 2004

A series of novel open‐chain and cyclic conformationally constrained (R)‐ and (S)‐α,α‐disubstituted tyrosine analogues 1a–e were synthesized in good yields and high optical purities (Schemes 1 and 2). The absolute configurations of these tyrosine analogues were unambiguously determined based on the X‐ray structures of the precursor diastereoisomeric peptides of type 4 and 5. Four of these structures are described (Figs. 1–4), showing β‐turn type‐I geometries for dipeptides 4a, 5b, and 4c and an extended conformation for peptide 5c (Table 3). The conversion of the free amino acids 1a–c into suitably protected building blocks 11a–d and 15d,e for peptide synthesis is discussed (Schemes 3 and 4).
Synthesis and Reductive Complexation Properties of a Cone‐Configurated Tetra[p‐(tert‐butyl)]calix[4]arene incorporating bipyridyl and pyridine subunits. NMR characterization and crystal structure of its chiral copper(I) complex
Authors: Regnouf De Vains Jean‐Bernard , Lamartine Roger , Fenet Bernard , Bavoux Claude , Thozet Alain , Perrin Monique
Published: December 2004

The hetero‐armed p(tert‐butyl)calix[4]arene 1 was synthesized by a stepwise procedure. This ligand presented a very strong complexing behavior towards Cu1, giving the chiral complex 2 and parent species when reacted with CuII salts. High‐resolution NMR techniques were employed for the characterization of 2, demonstrating notably exchange processes between its two enantiomeric forms. The racemic nature of 2 was confirmed by X‐ray crystal‐structure analysis.
Bortrifluorid‐katalysierte Umsetzungen von 3‐Amino‐2H‐azirinen mit Aminosäure‐estern und Aminen
Authors: Hugener Martin , Heimgartner Heinz
Published: December 2004

Boron‐Trifluoride‐Catalyzed Reactions of 3‐Amino‐2H‐azirines with Amino‐acid Esters and Amines

After activation by protonation or complexation with BF3, 3‐amino‐2H‐azirines 1 react with the amino group of α‐amino‐acid esters 3 to give 3,6‐dihydro‐5‐aminopyrazin‐2(1H)‐ones 4 by ring enlargement (Scheme 2, Table 1). The configuration of 3 is retained in the products 4. With unsymmetrically substituted 1 (R1 ≠ R2), two diastereoisomers of 4 (cis and trans) are formed in a ratio of 1:1 to 2:1. With β‐amino‐acid esters 5 and 7, only openchain α‐amino‐imidamides 6 and 8, respectively, are formed, but none of the seven‐membered heterocycle (Scheme 3). Primary amines also react with BF3‐complexed 1 to yield α‐amino‐imidamides of type 9 (Scheme 4, Table 2). Compound 9b is characterized chemically by its transformation into crystalline derivatives 10 and 12 with 4‐nitrobenzoyl chloride and phenyl isothiocyanate, respectively (Scheme 5). The structure of 12 is established by X‐ray crystallography. Mechanisms for the reaction of activated 1 with amino groups are proposed in Schemes 6 and 7.
Diazo‐Transfer Reaction with Diphenyl Phosphorazidate
Authors: Villalgordo José M. , Enderli Adelheid , Linden Anthony , Heimgartner Heinz
Published: December 2004

Diphenyl phosphorazidate (DPPA) was used as the azide source in a one‐pot synthesis of 2,2‐disubstituted 3‐amino‐2H‐azirines 1 (Scheme 1). The reaction with lithium enolates of amides of type 2, bearing two substituents at C(2), proceeded smoothly in THF at 0°; keteniminium azides C and azidoenamines D are likely intermediates. Under analogous reaction conditions, DPPA and amides of type 3 with only one substituent at C(2) gave 2‐diazoamides 5 in fair‐to‐good yield (Scheme 2). The corresponding 2‐diazo derivatives 6–8 were formed in low yield by treatment of the lithium enolates of N,N‐dimethyl‐2‐phenylacetamide, methyl 2‐phenylacetate, and benzyl phenyl ketone, respectively, with DPPA. Thermolysis of 2‐diazo‐N‐methyl‐N‐phenylcarboxamides 5a and 5b yielded 3‐substituted 1,3‐dihydro‐N‐methyl‐2H‐indol‐2‐ones 9a and 9b, respectively (Scheme 3). The diazo compounds 5–8 reacted with 1,3‐thiazole‐5 (4H)‐thiones 10 and thiobenzophenone (13) to give 6‐oxa‐1,9‐dithia‐3‐azaspiro[4.4]nona‐2,7‐dienes 11 (Scheme 4) and thiirane‐2‐carboxylic acid derivatives 14 (Scheme 5), respectively. In analogy to previously described reactions, a mechanism via 1,3‐dipolar cycloaddition, leading to 2,5‐dihydro‐1,3,4‐thiadiazoles, and elimination of N2 to give the ‘thiocarbonyl ylides’ of type H or K is proposed. These dipolar intermediates with a conjugated CO group then undergo either a 1,5‐dipolar electrocyclization to give spirohetrocycles 11 or a 1,3‐dipolar electrocyclization to thiiranes 14.
Syntheses of Biphenyl Analogues of AP7, a New Class of Competitive N‐Methyl‐D‐aspartate (NMDA) Receptor Antagonists
Authors: Müller Werner , Kipfer Peter , Lowe David A. , Urwyler Stephan
Published: December 2004

Syntheses of a series of enantiomerically pure, substituted analogues 7b–t of SDZ EAB 515 (7a) were described (Schemes 1 and 2). Affinites for the NMDA receptor were measured ([3H]CGP‐39653 binding assay) and competitive NMDA antagonistic potencies determined in a functional test (rat neocortical slice preparation). Structure‐activity relationships show that attachment of an OH group at position 4 of the chain‐inserted benzene ring of the biphenyl moiety and/or expansion of the angle between the planes of the two benzene rings by ortho‐substituents increase in vitro activities into the low nanomolar range.
Die Reduktion von Azulen mit Natrium zum Kontaktionen‐Tripel [Dinatrium‐(1,1′,6,6′‐Tetrahydro‐6,6′‐bi(azulen)‐1,1′‐diid)–bis (diglyme)]∞
Authors: Bock Hans , Arad Claudia , Näther Christian , Göbel Ilka
Published: December 2004

The Sodium Reduction of Azulene to the Contact‐Ion Triple [Disodium‐(1,1′,6,6′‐Tetrahydro‐6,6′‐bi(azulene)‐1,1′‐diide)–bis(diglyme)]∞

Colorless air‐sensitive single crystals can be grown from a diglyme solution after the reduction of azulene by a Na‐metal mirror. Structure determination at 150 K reveals a dimer dianion, in which the seven‐membered rings are connected in 6,6′‐positions and doubly diglyme‐solvated Na+ counter cations η5‐coordinate to the five‐membered rings. Based on preceding cyclovoltammetric measurements in aprotic azulene solutions as well as on extensive MNDO enthalpy of formation calculations, a proposal is forwarded how possibly the contact ion triple is formed along a microscopic pathway.
Preparation, Structure, and Reactivity of Thioxo and Imino Derivatives of the Triolide (and Pentolide) from (R)‐3‐Hydroxybutanoic Acid
Authors: Brunner Andreas , Kühnle Florian N. M. , Seebach Dieter
Published: December 2004

Reaction of the triolide 1 from (R)‐3‐hydroxybutanoic acid with Lawesson's reagent 5 leads to the mono‐, di‐, and trithio derivatives 6–8 which can be isolated in pure form (20–40% yields), and which have crystal structures very similar to the parent triolide 1 (Fig. 1). Similarly, pentolide 3 is converted to mixtures of various thio derivatives, three of which are separated (10–12) by HPLC and fully characterized. The X‐ray structures of the mono‐ and of one of the dithiopentolides (10, 12) differ remarkably from each other (Fig. 3). Reduction of the thiotriolides 6–8 (NaBH4, R3SnH, Cl3SiH, Raney‐Ni) gives 12‐membered rings containing up to three ether groups (chiral crown ethers, 15, 17–19) in poor yields. The thiotriolides react spontaneously and in yields of up to 96% with ammonia, certain primary amines, and hydroxylamine to give imine and oxime derivatives with intact 12‐membered‐ring backbones (20, 22–24, 30, see crystal structures in Figs. 4–7). The rigid structure of all the derivatives of triolide 1 puts the CO, CS, and CNR O‐, S‐, and N‐atoms in juxtaposition (a feature reminiscent of the side chains in the iron‐binder enterobactin, Fig. 6). Imines containing PPh2 groups are prepared (30, 33, 35) from the thiotriolides and tested as chiral ligands for PdII‐catalyzed 1,3‐diphenyallylations (→ 37, enantiomer ratio up to 77:23). The reactions described demonstrate that multiple reactions of the triolide 1 from (R)‐3‐hydroxybutanoic acid which proceed through tetrahedral intermediates are possible without ring opening – the skeleton is remarkably stable, and this might be exploited as a template for bringing up to three pendent substituents into close proximity to allow a study of their interactions and cooperative properties. Also, the di‐ and trithio derivatives 7 and 8 could be used for cross‐linking in molecules containing primary NH2 groups.
Channel‐Forming Activity of 3‐Hydroxybutanoic‐Acid Oligomers in Planar Lipid Bilayers
Authors: Seebach Dieter , Brunner Andreas , Michael Büger H. , Reusch Rosetta N. , Bramble Linda L.
Published: December 2004

Monodisperse and polydisperse oligomers and polymers of 3‐hydroxybutanoic acid (3‐HB) containing 8, 16, ca. 28, 32, ca. 60, 64, 96, and ca. 3000 monomer units were incorporated into palmitoyl‐oleoyl‐phosphatidyl choline (POPC) planar bilayers. At concentrations of 0.1–5% of oligo(3‐HB), the resulting phospholipid bilayers showed typical single‐channel behavior for Rb+ and Ba2+ ions, using the patch clamp technique. Thus, channel‐forming activity of a pure polyester has been demonstrated for the first time (Figs. 1, 3, and 6). Single‐channel activity depends upon the following structural parameters of the 3‐HB derivatives: unprotected OH and COOH groups on the chain ends; chain length ⩾ 16 monomer units; no high‐molecular‐weight as in P(3‐HB). The results are discussed in view of the Ca2+‐specific channel formed with the P(3‐HP)/Ca · PPi complex from genetically competent Escherichia coli and in view of the ubiquitous occurrence of low‐molecular‐weight P(3‐HB) in prokaryotic and eukaryotic organisms. A simple model for the channel‐causing structure is proposed, based on the proven tendency of oligo‐ and poly(3‐HB) to form ca. 50‐Å thick lamellar crystallites.
Hydrolytic Breakdown of the Euplotins, Highly Strained, Adaptive, Hemiacetal Esters of the Marine Ciliate Euplotes crassus: A Mimic of Degradative Pathways in Nature and a Trick for the Assignment of the Absolute Configuration
Authors: Guella Graziano , Pietra Francesco , Dini Fernando
Published: December 2004

Euplotin C((+)‐3), the most abundant of the niche‐exploitation terpenoids of the marine ciliate morphospecies Euplotes crassus, was found to undergo degradation in mildly basic H2O/MeOH by initial hydrolysis of the acetate group, followed by, in turn, hydrolytic ring‐A and ring‐C opening and ring‐A reclosure with indiscriminate C(1)/C(15) methanol trapping to give four diastereoisomeric aldehydic hemiacetals 5–8 in similar proportions; 7, as a model for its congeners, proved biologically inactive. From these, the absolute configuration was assigned via Mosher's ester methodology. These processes may be assumed to mimic inactivation of the euplotins in sea water. Degradation of (+)‐3 in either stronger base or acidic medium was also examined.
Nonreductive Enantioselective Ring Opening of N‐(Methylsulfonyl)dicarboximides with Diisopropoxytitanium α,α,α′,α′‐Tetraaryl‐1,3‐dioxolane‐4,5‐dimethanolate
Authors: Ramón Diego J. , Guillena Gabriela , Seebach Dieter
Published: December 2004

The bicyclic and tricyclic meso‐N‐(methylsulfonyl)dicarboximides 1a–f are converted enantioselectively to isopropyl [(sulfonamido)carbonyl]‐carboxylates 2a–f by diisopropoxytitanium TADDOLate (75–92% yield; see Scheme 3). The enantiomer ratios of the products are between 86:14 and 97:3, and recrystallization from CH2Cl2/hexane leads to enantiomerically pure sulfonamido esters 2 (Scheme 3). The enantioselectivity shows a linear relationship with the enantiomer excess of the TADDOL employed (Fig.3). Reduction of the ester and carboxamide groups (LiAlH4) and additional reductive cleavage of the sulfonamido group (Red‐Al) in the products 2 of imide‐ring opening gives hydroxy‐sulfonamides 3 and amino alcohols 4, respectively (Scheme 4). The absolute configuration of the sulfonamido esters 2 is determined by chemical correlation (with 2a,b; Scheme 6), by the X‐ray analysis of the camphanate of 3e (Fig. 1), and by comparative 19F‐NMR analysis of the Mosher esters of the hydroxy‐sulfonamides 3 (Table 1). A general proposal for the assignment of the absolute configuration of primary alcohols and amines of Formula HXCH2CHR1R2, X = O, NH, is suggested (see 11 in Table 1). It follows from the assignment of configuration of 2 that the Re carbonyl group of the original imide 1 is converted to an isopropyl ester group. This result is compatible with a rule previously put forward for the stereochemical course of reactions involving titanium TADDOLate activated chelating electrophiles (12 in Scheme 7). A tentative mechanistic model is proposed (13 and 14 in Scheme 7).
Oligosaccharide Analogues of Polysaccharides. Part 8. Orthogonally Protected Cellobiose‐Derived Dialkynes. A Convenient Method for the Regioselective Bromo‐ and Protodegermylation of Trimethylgermyl‐ and Trimethylsilyl‐protected Dialkynes
Authors: Ernst Alexander , Vasella Andrea
Published: December 2004

The cellobiose‐derived dialkynes 14 and 15 were prepared by glycosidation of the acceptor 9 with the thioglycosides 12(82%) and 13(85%), respectively. The acceptor 9 was prepared from the known alcohol 2 via the lactone 7 in five steps (48% overall), and the donors 12 and 13 were prepared from the alkynylated anhydroglucose derivative 10 (60% overall). Acetolytic debenzylation of 14 and 15 (→16 and 17, resp.) followed by deacylation of 16 yielded 60% of the cellobiose‐derived dialkyne 18. Deacylation of 14 (→19), methoxymethylation (→20) and trimethylgermylation led to the orthogonally protected dialkyne 21 (69% overall). Protodesilylation of 21 with K2CO3/MeOH gave 22 (90%), while the Me3Ge group was selectively removed with CuBr (19 mol‐%) in THF/MeOH to give 20 (95%). Treatment of 21 with aqueous HCl solution led to 19 (80%). Bromodegermylation of 21 (NBS/AgOOCCF3) led to a mixture of 23 (85%) and 24 (11%). Similar conditions using CuBr instead of AgOOCCF3 gave exclusively the bromoalkyne 23 (93%). The temperature dependence of the δ values of the OH resonances of 18 in (D6)DMSO evidence a strong intramolecular H‐bond between C(5′)O…︁HOC(5).
Synthese von Trifluoromethyl‐substituierten Schwefel‐Heterocyclen unter Verwendung von 3,3,3‐Trifluorobrenztraubensäure‐Derivaten
Authors: Mlostoń Grzegorz , Gendek Tomasz , Heimgartner Heinz
Published: December 2004

Synthesis of Trifluoromethyl‐Substituted Sulfur Heterocycles Using 3,3,3‐Trifluoropyruvic‐Acid Derivatives

The reaction of methyl 3,3,3‐trifluoropyruvate (1) with 2,5‐dihydro‐1,3,4‐thiadiazoles 4a, b in benzene at 45° yielded the corresponding methyl 5‐(trifluoromethyl)‐1,3‐oxathiolane‐5‐carboxylates 5a, b (Scheme 1) via a regioselective 1,3‐dipolar cycloaddition of an intermediate ‘thiocarbonyl ylide’ of type 3. With methyl pyruvate, 4a reacted similarly to give 6 in good yield. Methyl 2‐diazo‐3,3,3‐trifluoropropanoate (2) and thiobenzophenone (7a) in toluene underwent a reaction at 50°; the only product detected in the reaction mixture was thiirane 8a (Scheme 2). With the less reactive thiocarbonyl compounds 9H‐xanthene‐9‐thione (7b) and 9H‐thioxanthene‐9‐thione (7c) as well as with 1,3‐thiazole‐5(4H)‐thione 12, diazo compound 2 reacted only in the presence of catalytic amounts of Rh2(OAc)4. In the cases of 7a and 7b, thiiranes 8b and 8c, respectively, were the sole products (Scheme 3). The crystal struture of 8c has been established by X‐ray crystallography (Fig.). In the reaction with 12, desulfurization of the primarily formed thiirane 14 gave the methyl 3,3,3‐trifluoro‐2‐(4,5‐dihydro‐1,3‐thiazol‐5‐ylidene)propanoates (E)‐and (Z)‐15 (Scheme 4). A mechanism of the Rh‐catalyzed reaction via a carbene addition to the thiocarbonyl S‐atom is proposed in Scheme 5.
A Non‐Racemic Equivalent of Glycolic Acid: Preparation of both enantiomers from D‐mannitol
Authors: Renaud Philippe , Abazi Sokol
Published: December 2004

A practical synthesis of both enantiomers of 2‐(tert‐butyl)‐2‐methyl‐1,3‐dioxolan‐4‐one starting from D‐mannitol is reported. These compounds are chiral equivalents of glycolic acid (= hydroxyacetic acid) which are configurationally stable and can be alkylated via their enolates.
Mechanistic Details of the Fe+‐Mediated CC and CH Bond Activations in Propane: A Theoretical Investigation
Authors: Holthausen Max C. , Koch Wolfram
Published: December 2004

Quantum‐chemical calculations employing a density‐functional theory/Hartree‐Fock hybrid method (B3LYP) have been used to explore the mechanistic details of the CC and CH bond‐activation processes in propane mediated by a bare Fe+ ion. While the theoretically predicted results are in complete accord with all available experimental data, they give rise to a different mechanistic picture than envisaged previously. In contrast to earlier speculation, the activation barriers for the initial insertion steps of Fe+ into a CH or CC bond are found to be significantly below the Fe+ + C3H8 channel. The rate‐determining steps for both, the CC and the CH bond activation branches of the [FeC3H8]+ potential‐energy surface rather occur late on the respective reaction coordinates and are connected with saddle points of concerted rearrangement processes. The CC bond activation, which leads to the exothermic reductive elimination of methane, occurs via the CC inserted species and not as a side channel originating from a CH inserted ion, as assumed hitherto. For the CH bond‐activation processes, which finally results in the exothermic expulsion of molecular hydrogen, two energetically similar reaction channels for an [1,2]‐elimination exist. The results clearly show, that an [1,3]‐H2‐elimination mechanism cannot compete with the [1,2]‐elimination paths, in line with the experimental findings. Overall, a lower energy demand for the reductive elimination of methane compared to the loss of H2 is obtained, straightforwardly explaining the preference of the former process observed experimentally.
Oligosaccharide Analogues of Polysaccharides. Part 9. Synthesis and Thermolysis of Acetylenosaccharide‐Derived 1,2‐Dialkynylbenzenes
Authors: Xu Jinwang , Egger Anita , Bernet Bruno , Vasella Andrea
Published: December 2004

Thermolysis of the 1,2‐bis(glucosylalkynyl)benzenes 6 and 16 was studied to evaluate the effects of intramolecular H‐bonding on the activation energy of the Bergman‐Masamune‐Sondheimer cycloaromatization, and to evaluate the use of the cycloaromatization for the synthesis of di‐glycosylated naphthalenes. The dialkynes were prepared by cross‐coupling of the O‐benzylated or O‐silylated glucosylalkynes 1 and 4 (Scheme 1). Thiolysis of the known 1, or acetolysis of 1, followed by deacetylation (→2→3) and silylation gave 4. Cross‐coupling of 1 or 4 with iodo‐ or 1,2‐diiodobezene depended upon the nature of the added amine and on the protecting group, and led to the mono‐ and dialkynylbenzenes 5 and 6, or 12, 13, and 15, respectively. The benzyl ethers 5 and 6 gave poor yields upon acetolysis catalyzed by BF3 · OEt2, while Ac2O/CoCl2 · 6 H2O transformed 6 in good yields into the regioselectively debenzylated 10. Desilylation of 7 and 13 gave the alcohols 8 and 14, respectively. Thermolysis of 6 in PhCl gave 22 and 23, independently of the presence or absence of 1,4‐cyclohexadiene; 23 was formed from 22 (Scheme 2). Acetolysis of 22 gave the hexaacetate 24 that was completely debenzylated by thiolysis, yielding the diol 26 and trans‐stilbene, evidencing the nature and position of the bridge between the glucosyl moieties (Scheme 3). Thiolysis of 22 yielded the unprotected 2,3‐diglucosylnaphthalene 28, a new type of C‐glycosides. Depending upon conditions, hydrogenation of 22 led to 29 (after acetylation), 30, or 32. NMR and particularly NOE data evidence the threo‐configuration of the bridge. The structure of 23 was confirmed by hydrolysis to the diol 34 and diphenylacetaldehyde, and by correlation of 23 with 22 via the common product 31. Formation of 22 is rationalized by a Bergman cyclization to a diradical, followed by regioselective abstraction of a H‐atom from the BnOC(2) group, and diastereoselective combination of the doubly benzylic diradical (Scheme 4). While thermolysis of 3 in EtOH sets in around 140°, 16 did not react at 160° and decomposed at 180–220°. No evidence for intramolecular H‐bonds of 16, as compared to 14, were found.
Probing the Helical Secondary Structure of Short‐Chain β‐Peptides
Authors: Seebach Dieter , Ciceri Paola E. , Overhand Mark , Jaun Bernhard , Rigo Dario , Oberer Lukas , Hommel Ulrich , Amstutz René , Widmer Hans
Published: December 2004

Structural prerequisites for the stability of the 31 helix of β‐peptides can be defined from inspection of models (Figs. 1 and 2): lateral non‐H‐substituents in 2‐ and 3‐position on the 3‐amino‐acid residues of the helix are allowed, axial ones are forbidden. To be able to test this prediction, we synthesized a series of heptapeptide derivatives Boc‐(β‐HVal‐β‐HAla‐β‐HLeu‐Xaa‐β‐HVal‐β‐HAla‐β‐HLeu)‐OMe 13–22 (Xaa = α‐ or β‐amino‐acid residue) and a β‐depsipeptide 25 with a central (S)‐3‐hydroxybutanoic‐acid residue (Xaa = –OCH(Me)CH2C(O)–) (Schemes 1 3). Detailed NMR analysis (DQF‐COSY, HSQC, HMBC, ROESY, and TOCSY experiments) in methanol solution of the β‐hexapeptide H(‐β‐HVal‐β‐HAla‐β‐HLeu)2‐OH (1) and of the β‐heptapeptide H‐β‐HVal‐β‐HAla‐β‐HLeu‐(S,S)‐β‐HAla(αMe)‐β‐HVal‐β‐HAla‐ β‐HLeu‐OH (22), with a central (2S,3S)‐3‐amino‐2‐methylbutanoic‐acid residue, confirm the helical structure of such β‐peptides (previously discovered in pyridine solution) (Fig.3 and Tables 1–5). The CD spectra of helical β‐peptides, the residues of which were prepared by (retentive) Arndt‐Eistert homologation of the (S)‐ or L‐α‐amino acids, show a trough at 215 nm. Thus, this characteristic pattern of the CD spectra was taken as an indicator for the presence of a helix in methanol solutions of compounds 13–22 and 25 (including partially and fully deprotected forms) (Figs.4–6). The results fully confirm predicted structural effects: incorporation of a single ‘wrong’ residue ((R)‐β‐HAla, β‐HAib, (R,S)‐β‐HAla(α Me), or N‐Me‐β‐HAla) in the central position of the β‐heptapeptide derivatives A (see 17, 18, 20, or 21, resp.) causes the CD minimum to disappear. Also, the β‐heptadepsipetide 25 (missing H‐bond) and the β‐heptapeptide analogs with a single α‐amino‐acid moiety in the middle (13 and 14) are not helical, according to this analysis. An interesting case is the heptapeptide 15 with the central achiral, unsubstituted 3‐aminopropanoic‐acid moiety: helical conformation appears to depend upon the presence or absence of terminal protection and upon the solvent (MeOH vs. MeOH/H2O).
Biosynthesis of δ‐Jasmin Lactone ( = (Z)‐Dec‐7‐eno‐5‐lactone) and (Z,Z)‐Dodeca‐6,9‐dieno‐4‐lactone in the Yeast Sporobolomyces odorus
Authors: Haffner Thomas , Nordsieck Andreas , Tressl Roland
Published: December 2004

(all‐Z)‐(9,10,12,13,15,16‐2H6)Octadeca‐9,12,15‐trienoic acid ( = α‐linolenic acid; D6‐4) was synthesized to investigate the biochemical formation of linolenic‐acid‐derived aroma compounds in cultures of the yeast Sporobolomyces odorus, using an established gas chromatographic/mass spectrometric (GC/MS) method. Three compounds were identified as labeled: (Z)‐dec‐7‐eno‐5‐lactone (δ‐jasmin lactone), (Z,Z)‐dodeca‐6,9‐dieno‐4‐lactone, and (2E,4Z)‐hepta‐2,4‐dienoic acid. Both lactones were biosynthesized mostly under conservation of the initial configuration from their corresponding oxygenated linolenic‐acid intermediates. The application of (13S,9Z,11E,15Z)‐13‐hydroxy(9,10,12,13,15, 16‐2H6)octadeca‐9,11,15‐trienoic acid (D6‐7) as a OH‐functionalized precursor of δ‐jasmin lactone allowed to gain insight into the stereochemical course of the biosynthesis to both enantiomers of this lactone. In this experiment, 88.3% of the metabolized labeled precursor was transformed under retention of the original configuration of the (R)‐enantiomer. This investigation is also a contribution to a better understanding of the CC bond isomerization steps which took place during the β‐oxidative degradation of the substrate.
Nucleosides. Part LXI. A Simple Procedure for the Monomethylation of Protected and Unprotected Ribonucleosides in the 2′‐O‐ and 3′‐O‐Position Using Diazomethane and the Catalyst Stannous Chloride
Authors: Cramer Hagen , Pfleiderer Wolfgang
Published: December 2004

Intensive studies on the diazomethane methylation of the common ribonucleosides uridine, cytidine, adenosine, and guanosine and its derivatives were performed to obtain preferentially the 2′‐O‐methyl isomers. Methylation of 5′‐O‐(monomethoxytrityl)‐N2‐(4‐nitrophenyl)ethoxycarbonyl‐O6‐[2‐(4‐nitrophenyl)ethyl]‐guanosine (1) with diazomethane resulted in an almost quantitative yield of the 2′‐ and 3′‐O‐methyl isomers which could be separated by simple silica‐gel flash chromatography (Scheme 1). Adenosine, cytidine, and uridine were methylated with diazomethane with and without protection of the 5′ ‐O‐position by a mono‐ or dimethoxytrityl group and the aglycone moiety of adenosine and cytidine by the 2‐(4‐nitrophenyl)ethoxycarbonyl (npeoc) group (Schemes 2–4). Attempts to increase the formation of the 2′‐O‐methyl isomer as much as possible were based upon various solvents, temperatures, catalysts, and concentration of the catalysts during the methylation reaction.
Development of Luminescent Terbium(III) Chelates for Protein Labelling: Effect of triplet‐state energy level
Authors: Takalo Harri , Mukkala Veli‐Matti , Meriö Liisa , Rodríguez‐Ubis Juan Carlos , Sedano Rosa , Juanes Olga , Brunet Ernesto
Published: December 2004

The synthesis of novel TbIIIlabels suitable for protein labelling are reported. Their luminescence properties as antibody conjugates were measured and compared to the results of corresponding TbIIIchelates of the parent ligand structures. When the lowest triplet‐state energy level of the parent donor ligand was over 23000 cm−1,i.e., the energy gap between the5D4level of TbIIIand the lowest triplet‐state energy level of the ligand exceeded 2600 cm−1, the label derivative with a long decay time (τ = 1.35–2.93 ms) and a high luminescence yield (ϵ. Φ = 3770–4560) was found to be suitable for bioaffinity assays.
Diastereoselective Synthesis of Cyclododeca‐1,6‐diallenes ( = cyclododeca‐l,2,6,7‐tetraenes)
Authors: Boss Christoph , Keese Reinhart
Published: December 2004

The synthesis of substituted cyclododeca‐1,6‐diallenes.( = cyclododeca‐1,2,6,7‐tetraenes) from cyclododeca‐5,11‐diyne‐1,4‐diols is described (Schemes 1 and 3). The ca. 1:1 mixtures of the stereoisomers of the cyclododeca‐1,6‐diallenes were formed in high yields from the ca. 1:1 diastereoisomer mixtures of the 1,4‐disubstituted cyclododeca‐5,11‐diynes by reactions with Me2CuLi or t‐BuMgCl/CuII. In mechanistically relevant experiments with the pure diastereoisomers of 1,4‐dimethylcyclododeca‐5,11‐diyne‐1,4‐diol, it is demonstrated that the configuration is conserved in these reactions. The first synthesis of a 1‐substituted cyclododeca‐2,8‐diyne bearing only one propargylic leaving group gives access to a mixed 12‐membered allen‐yne (Scheme 5).
Stereochemistry of the Inhibition of δ‐Chymotrypsin with Optically Active Bicyclic Organophosphates: 31P‐NMR studies
Authors: Ganci Walter , Meier Eric J. M. , Merckling Franco A. , Przibille Georg , Ringeisen Urs , Rüedi Peter
Published: December 2004

The inhibition of δ‐chymotrypsin with optically active, axially and equatorially substituted trans‐3‐(2,4‐dini‐trophenoxy)‐2,4‐dioxa‐3λ5‐phospbubicyclo[4.4.0]decan‐3‐ones ( = hexahydro‐4H‐1,3,2‐benzodioxaphosphorin 3‐oxides) was investigated. Their inhibitory power was determined by kinetic measurements, and the stereochemical course of the reaction of stoichiometric amounts of the enzyme and inhibitor was monitored with 31P‐NMR spectroscopy at pH 7.8. The irreversible inhibitors show significant enantioselectivity (the (Sp)‐enantiomer reacting faster) and yield diastereoisomeric, covalently phosphorylated derivatives of δ‐chymotrypsin.

31P‐NMR Spectroscopic studies of the inhibition by the axially substituted inhibitor revealed for the racemic (±)‐2a first a resonance at –4.4 ppm and later, while inhibition proceeded, a second one at –4.5 ppm. The reaction with optically active (+)‐2a showed only one signal at –4.4 ppm and its enantiomer (–)‐2a only one signal at –4.5 ppm. Using the equatorially substituted racemic epimer (±)‐2b, we observed the main resonance at –5.3 ppm and two minor ones at –4.4 and –4.5 ppm. The optically active compound (+)‐2b showed two peaks at –4.5 and –5.3 ppm, whereas its antipode (–)‐2b revealed two signals at –4.4 and –5.3 ppm.

Comparing the 31P chemical shifts of the corresponding covalent phosphoserine derivatives 4a (‐5.7 ppm, axial) and 4b (‐4.5 ppm, equatorial) shows the inhibition with the axial compounds 2a to proceed via neat inversion of the configuration at the P‐atom, whereas the equatorial epimers 2b with a higher conformational flexibility seem to follow a different stereochemical pathway which results in both inversion and retention.
Lipophilicity Behavior of Model and Medicinal Compounds containing a suilfide, sulfoxide, or sulfone moiety
Authors: Caron Giulia , Gaillard Patrick , Carrupt Pierre‐Alain , Testa Bernard
Published: December 2004

This study was designed to unravel lipophilicity changes associated with the oxidation state of the S‐atom in model compounds, drugs, and metabolites, special attention being given both to intermolecular and intramolecular effects. The methods used were experimental (potentiometry, CPC, and shake‐flask techniques to measure lipophilicity, 13C‐NMR spectroscopy to investigate tautomeric equilibria) and computational (quenched molecular dynamics and molecular lipophilicity potential). Simple, monofunctional model compounds were used to assess intermolecular forces, as revealed by the Δlog Poct–alk and Δlog Poct–chf parameters. Drugs and their metabolites proved to be good probes to study intramolecular effects in both neutral and anionic forms, as revealed by the difference between calculated and experimental log Poct values (the diff(log Pexp–calc) parameter). Sulindac and its metabolites showed a normal partitioning behavior, whereas the lipophilicity of sulfmpyrazone and its metabolites' was markedly affected by tautomeric and conformational equilibria.
Elektronentransfer und Ionenpaar‐Bildung. 46. Mitteilung. Titrationen von Tetracyanethen mit Alkali‐ und Erdalkalimetallen in aprotischen Lösungen
Authors: Bock Hans , Kleine Markus
Published: December 2004

Electron Transfer and Ion‐Pair Formation: Titrations of Tetracyanoethene by Alkaline and Alkaline Earth Metals in Aprotic Solution

For alkaline and earth alkaline metal ‘titrations’ of the π‐acceptor tetracyanoethene in aprotic (c(H⊕) < 0.1 ppm) solution, UV/VIS and ESR spectra have been measured in a sealed glas apparatus. Isosbestic points prove uniform but differing metal‐mirror reduction processes for [Li]x, [Na]x, and [K]x vs. [Cs]x. The formation of solvent‐shared or solvent‐separated contact ion pairs detected is supported by subsequent crystallization and structure determination. For the tetracyanoethene radical anion, semiempirical PM3 calculations with limited configuration interaction allow to reproduce the structural data as well as the long‐wavelength charge transfer excitation.
An Efficient Synthesis of Enantiomerically Pure Δ‐ and Δ‐Ruthenium(II)‐Labelled Oligonucleotides
Authors: Meggers Eric , Kusch Dirk , Giese Bernd
Published: December 2004

The synthesis of a novel tris(bidentate ligand)ruthenium(II) complex 7 and its efficient tethering to the 5′‐end of Oligonucleotides is described. The resulting Δ‐ and Δ‐isomeric ruthenium(II)‐labelled Oligonucleotides 10a‐‐c and 11a‐‐d were separated either by reversed‐phase HPLC or by polyacrylamide gel electrophoresis. The diastereoisomerically pure isomers were fully characterized by UV/VIS and CD spectroscopy, mass spectrometry, and enzymatic digestion with base analysis. We also investigated the thermal denaturation of the hybridized double strands.
Properties and Reactions of Substituted 1,2‐Thiazetidine 1,1‐Dioxides: Synthesis ofN‐Substituted 4,4‐dimethyl‐1,2‐thiazetidin‐3‐one 1,1‐dioxides, and a new base‐catalyzed rearrangement to thiazolidin‐4‐one 1,1‐dioxides
Authors: Glasl Dietmar , Otto Hans‐Hartwig , Rihs Grety
Published: December 2004

Alkylation of 3‐oxo‐1,2‐thiazetidine 1,1‐dioxide 2 yields theN‐alkylated 3‐oxo‐β‐sultams3a‐i. Solvolysis with NaOH or NH3selectively opens the NS bond forming the sulfonate carboxamides4and the sulfonamidocarboxamides7, respectively. Furthermore, the hitherto unknown compounds of type5are prepared, representing a strained four‐membered ring with a diacylated, sulfonated N‐atom. Depending upon the reaction conditions,3b‐dand3gare rearranged by base‐catalyzed reactions into the substituted 4‐oxothiazolidine 1,1‐dioxides9or10.Structures are elucidated by spectroscopic methods, established by crystal‐structure analyses, and a possible way of formation is proposed. Furthermore, some side reactions and transformations are reported.
Synthesis of Chiral Bicyclic Bis‐lactam Components for the controlled self‐assembly of hydrogen‐bonded arrays
Authors: Brienne Marie‐JosèPhe , Gabard Jacqueline , Leclercq Martine , Lehn Jean‐Marie , Chevé Michel
Published: December 2004

The chiral biyclic bis‐lactams of structures 3 and 4 were synthesized from the key intermediate 2′b, the N,N′‐bis(4‐methoxybenzyl) derivative of 2 (X = MeO) (Scheme 6). The synthesis of this intermediate involved two key steps: (1) a double condensation of glyoxylic acid/anisamide (= oxoacetic acid/4‐methoxybenzamide) adduct 11c with veratrole (1,2‐dimethoxybenzene; 10) allowed the introduction of two glycine units at the 4,5‐positions of the veratrole ring to give 18c (Schemes 3 and 4); (2) in order to circumvent the hydrolysis of 4‐methoxybenzoyl protective groups which proved to be unfeasible, these groups were transformed into 4‐methoxybenzyl groups through a sequence involving thiocarbonylation followed by reduction (Scheme 5). Thereafter, the double intramolecular cyclization of the resulting diamino diester 22c proceeded easily to afford 2′b. This intermediate may be transformed via the tetrol 2′g or the diol 2′h into the N‐protected derivatives of 2 (X = OR) and of 3 (X = OCOR). Cleavage of the 4‐alkuxybenzyl groups was achieved by ceric ammonium nitrate. However, when the aromatic ring bore ether functions (N‐protected 2), this normal reaction was accompanied by the oxidative ring cleavage to give the diene‐diester structure 4 (Schemes 5 and 6).
Molecular Recognition and Enantiomer Separations on a novel chiral stationary phase based on a 9,9′‐spirobi[9H‐fluorene]‐derived molecular cleft
Authors: Cuntze Jens , Diederich François
Published: December 2004

An optically active molecular cleft incorporating a 9,9′‐spirobi[9H‐fluorene] spacer and two N‐(5,7‐dimethyl‐1,8‐naphthyridin‐2‐yl)carboxamide: (CONH(naphthyr)) moieties as H‐bonding sites was covalently bound to silica gel to provide the new chiral stationary phase (CSP) (R)‐16 (Scheme 2). Previous solution‐binding studies in CDCl3 had shown that the anchored molecular cleft was capable of complexing optically active dicarboxylic acids with differences in free energy of the formed diastereoisomeric complexes (Δ(ΔG0)) between 0.5 and 1.6 kcal mol−1 (T = 300 K). The optical resolution of racemic dicarboxylic acids, that are bound with a high degree of enantioselectivity in the liquid phase, was now achieved by HPLC on the CSP (R)‐16. The order of enantiomer elution was as predicted from the solution studies, and the separation factor α varied between 1.18 and 1.24. A series of 1,1′‐binaphthalene‐2,2′‐diol derivatives were also resolved on the new CSP, in some cases with baseline separation. The order of enantiomer elution under normal‐phase chromatographic conditions was rationalized by computer modeling of the association between the solute enantiomers and the immobilized molecular cleft. HPLC Separations with eluents of different polarity suggested that the attractive interactions between solute and immobilized chiral selector are a combination of H‐bonding, which prevails in apolar eluents, and aromatic π‐‐π stacking, which dominates in polar eluents.
Synthesis of Medium‐ and Large‐Ring Compounds Initiated by Photochemical Decarboxylation of ω‐Phthalimidoalkanoates
Authors: Griesbeck Axel G. , Henz Andreas , Kramer Wolfgang , Lex Johann , Nerowski Frank , Oelgemöller Michael , Peters Karl , Peters Eva‐Maria
Published: December 2004

The synthesis of a variety of hydroxylactams from ω‐phthalimidoalkanoates using a triplet‐sensitized photodecarboxylation reaction initiated by intramolecular photo electron transfer is described. Ring sizes available by this method span from 4 (benzazepine‐1,5‐dione 7) to 26 (cyclodipeptide 26e). Ground‐state template formation is proposed as the explanation for the high efficiency of this reaction and for the decrease in reactivity in the presence of organic bases instead of metal carbonates. The crucial step in this macrocyclization reaction seems to be the protonation of the intermediary ketyl radials (Scheme 4). Spacer groups investigated were alkyl chains (C3‐C11: 5c‐h, 11a, 12), ether (16, 18), ester (20, 22), and amide (26a‐f) linkages. Within the detection limits, no dimeric (= decarboxylative coupling) products were observed, indicating the high preference for intra‐vs. intermolecular photoelectron transfer. The C,C radical combination step proceeds with low stereoselectivity (cf, products 11 and 12) in contrast to comparable singlet reactions. Except for the lactones 22, all products were stable under the photolysis conditions. Prolonged irradiation of 22 led to the formation of the spiro compounds 23, probably via an intermediary acyliminium betaine (Scheme 8). One serious limitation of the decarboxylative macrocyclization is its incompatibility with the glycine spacer (as in 27a and 27b), probably the consequence of a strong intramolecular H‐bond (Scheme 10).
Nucleotides. Part LIII. 6‐Aminohexanoyl‐linked conjugates of monomeric and trimeric cordycepin
Authors: Wasner Marita , Pfleiderer Wolfgang , Suhadolnik Robert J. , Horvath Susan E. , Kon Ning , Guan Ming‐Xu , Henderson Earl E. , Adelson Martin E.
Published: December 2004

To improve cell permeability, monomeric 3′‐deoxyadenosine (cordycepin) and antivirally active trimeric 3′‐deoxyadenylyl‐(2′–5′)‐3′‐deoxyadenylyl‐(2′–5′)‐3′‐deoxyadenosine (2′–5′)d3 (A‐A‐A); (cordycepin‐trimer core) were modified at the 2′‐O‐ or 5′‐O‐position by myristic, cholic, and folic acid = tetradecanoic, 3α, 7α, 12α ‐trihy‐droxy‐5β‐cholan‐24‐oic, and N‐{4‐{[(2‐amino‐3,4‐dihydro‐4‐oxopteridin‐6‐yl)methyl]amino}benzoyl}‐L‐glutamic acid, resp., linked by a 6‐aminohexamoyl spacer. Syntheses of the trimeric educts 21, 27, and 28 were performed by phosphoramidite chemistry, using β‐eliminating 2‐(4‐nitrophenyl)ethyl (npe), 2‐(4‐nitrophenyl)ethoxycarbonyl (npeoc) and (9H‐fluoren‐9‐yl)methoxycarbonyl (fmoc) groups which allow a deprotection by DBU in an aprotic solvent without harming the ester‐bounded conjugates, to give the products 24–26 and 31–33. The metabollically stable (2′–5′)A derivatives 26 and 33, covalently linked to folic acid either at the 2′‐terminus or at the 5′‐terminus of (2′–5′)d3′(A‐A‐A), respectively, are a new class of the anti‐HIV‐1 compounds. Inhibition of HIV‐1 reverse transcriptase (RT) activity by 26 and 33 was 45 and 81%, respectively. Only 33 activated recombinant, human RNase L by 35%.