Helvetica Chimica Acta

Abele, Stefan; Vögtli, Kurt; Seebach, Dieter

doi: 10.1002/(SICI)1522-2675(19991006)82:10<1539::AID-HLCA1539>3.0.CO;2-Epmid: N/A

To study the role of H‐bonds in stabilizing β‐peptidic secondary structures, we have synthesized β‐oligopeptides (up to the octadecamer 12) consisting of β2‐ and β3‐homoproline, i.e., β‐peptides lacking amide protons. The enantiomer purity of the building block β2‐homoproline (nipecotic acid, 4) was determined by HPLC analysis of the N‐(2,4‐dinitrophenyl) derivative 5 on a Chiralcel‐OD column (cf. Fig. 2). The CD spectra of the all‐(S)‐β2‐ and all‐(S)‐β3‐HPro‐containing β‐peptides display novel and intensive CD patterns which may be indicative of a secondary structure (cf. Fig. 3). It is noteworthy that a distinct CD pattern was observed with the β3‐HPro derivatives containing as few as three residues (7a). The crystal structure of a N‐deprotected β3‐HPro‐tripeptide 7c is presented (cf. Figs. 4 and 5), and a model for the structure of β‐peptides consisting of β3‐HPro is discussed (cf. Figs. 6 and 7).

Abele, Stefan; Seiler, Paul; Seebach, Dieter

doi: 10.1002/(SICI)1522-2675(19991006)82:10<1559::AID-HLCA1559>3.0.CO;2-Apmid: N/A

Partially and fully protected, and unprotected β‐oligopeptides (3 – 9) were prepared from 1‐(aminomethyl)cyclopropanecarboxylic acid, which, in turn, is readily available from cyanoacetate and dibromoethane. N‐Boc and C‐OMe protection were applied for the fragment‐coupling (1‐hydroxy‐1H‐benzotriazole (HOBt)/1‐[3‐(dimethylamino)propyl]‐3‐ethylcarbodiimide hydrochloride (EDC)) solution synthesis. X‐Ray crystal structures of the dimer (3), trimer (5), and tetramer (6) are described, and compared with those of the Boc‐protected building blocks (2) and of the corresponding trimer (10) consisting of 1‐(aminomethyl)cyclohexanecarbonyl residues (cf. Figs. 1 and 2). While the cyclohexane derivative forms ten‐membered hydrogen‐bonded rings, the characteristic secondary‐structural motif in the cyclopropane derivatives is an eight‐membered ring with H‐bonding between next neighbors (Fig. 1). All cyclopropanecarbonyl moieties in the reported structures have the – generally more stable – s‐cis (`bisected') conformation of the C=O groups on the three‐membered rings (not preferred with the cyclohexane analog, the exocyclic CO group of which may be in an s‐trans, a perpendicular, an axial, or an equatorial position). The bisecting effect and the large exocyclic bond angle (120°) in the cyclopropane units are proposed to provide the `ordering' elements – on top of the staggering effect of the C(2)−C(3) ethane bond in all β‐peptides – which lead to the observed substituent‐induced turn formation. A high degree of intramolecular H‐bonding is evident also from IR spectroscopy (Fig. 3), and concentration‐ and temperature‐dependent NMR measurements (Fig. 4) of CHCl3 and CD2Cl2 solutions, indicating that the boat‐type arrangement of the eight‐membered rings with their unusual H‐bonding geometry (Fig. 1, f ) is also present in solution. A possible structure of a poly[1‐(aminomethyl)cyclopropane‐carboxylic acid] consisting of a flight of stairs formed by folded H‐bonded eight‐membered rings is modelled, using the oligomer X‐ray data (Fig. 5). The type of secondary structure found in the solid state of the β2,2‐peptides reported here is unprecedented in the realm of α‐peptides and proteins.

Bourgeois, Jean‐Pascal; Seiler, Paul; Fibbioli, Monia; Pretsch, Ernö; Diederich, François; Echegoyen, Luis

doi: 10.1002/(SICI)1522-2675(19991006)82:10<1572::AID-HLCA1572>3.0.CO;2-Bpmid: N/A

The fullerene‐crown ether conjugates (±)‐1 to (±)‐3 with trans‐1 ((±)‐1), trans‐2 ((±)‐2), and trans‐3 ((±)‐3) addition patterns on the C‐sphere were prepared by Bingel macrocyclization. The trans‐1 derivative (±)‐1 was obtained in 30% yield, together with a small amount of (±)‐2 by cyclization of the dibenzo[18]crown‐6(DB18C6)‐tethered bis‐malonate 4 with C60 (Scheme 1). When the crown‐ether tether was further rigidified by K+‐ion complexation, the yield and selectivity were greatly enhanced, and (±)‐1 was obtained as the only regioisomer in 50% yield. The macrocyclization, starting from a mixture of tethered bis‐malonates with anti (4) and syn (10) bisfunctionalized DB18C6 moieties, afforded the trans‐1 ((±)‐1, 15%), trans‐2 ((±)‐2, 1.5%), and trans‐3 ((±)‐3, 20%) isomers (Scheme 2). Variable‐temperature 1H‐NMR (VT‐NMR) studies showed that the DB18C6 moiety in C2‐symmetrical (±)‐1 cannot rotate around the two arms fixing it to the C‐sphere, even at 393 K. The planar chirality of (±)‐1 was confirmed in 1H‐NMR experiments using the potassium salts of (S)‐1,1′‐binaphthalene‐2,2′‐diyl phosphate ((+)‐(S)‐19) or (+)‐(1S)‐camphor‐10‐sulfonic acid ((+)‐20) as chiral shift reagents (Fig. 1). The DB18C6 tether in (±)‐1 is a true covalent template: it is readily removed by hydrolysis or transesterification, which opens up new perspectives for molecular scaffolding using trans‐1 fullerene derivatives. Characterization of the products 11 (Scheme 3) and 18 (Scheme 4) obtained by tether removal unambiguously confirmed the trans‐1 addition pattern and the out‐out geometry of (±)‐1. VT‐NMR Studies established that (±)‐2 is a C2‐symmetrical out‐out trans‐2 and (±)‐3 a C1‐symmetrical in‐out trans‐3 isomer. Upon changing from (±)‐1 to (±)‐3, the distance between the DB18C6 moiety and the fullerene surface increases and, correspondingly, rotation of the ionophore becomes increasingly facile. The ionophoric properties of (±)‐1 were investigated with an ion‐selective electrode membrane (Fig. 2 and Table 2), and K+ was found to form the most stable complex among the alkali‐metal ions. The complex between (±)‐1 and KPF6 was characterized by X‐ray crystal‐structure analysis (Figs. 3 and 4), which confirmed the close tangential orientation of the ionophore atop the fullerene surface. Addition of KPF6 to a solution of (±)‐1 resulted in a large anodic shift (90 mV) of the first fullerene‐centered reduction process, which is attributed to the electrostatic effect of the K+ ion bound in close proximity to the C‐sphere (Fig. 5). Smaller anodic shifts were measured for the KPF6 complexes of (±)‐2 (50 mV) and (±)‐3 (40 mV), in which the distance between ionophore and fullerene surface is increased (Table 3). The effects of different alkali‐ and alkaline‐earth‐metal ion salts on the redox properties of (±)‐1 were investigated (Table 4). These are the first‐ever observed effects of cation complexation on the redox properties of the C‐sphere in fullerene‐crown ether conjugates.

Tollinger, Martin; Konrat, Robert; Kräutler, Bernhard

doi: 10.1002/(SICI)1522-2675(19991006)82:10<1596::AID-HLCA1596>3.0.CO;2-Kpmid: N/A

The solution structure of methylcob(III)alamin (MeCbl; 3), a natural organometallic corrinoid‐B12 cofactor whose crystal structure was published in 1985, was established by NMR‐spectroscopic analyses of 3 in aqueous solution. The full set of unambiguously assigned 1H, 13C, and amide 15N signals was consistent with identical constitutional and configurational properties of 3 in solution and in the crystal. Specifically investigated were the conformational characteristics of 3 in solution, in particular of its unique Co‐coordinating nucleotide moiety. An extensive set of NOE‐derived distance constraints was acquired for this purpose, and of angle constraints, based on three‐bond coupling constants. These data were used to calculate the solution structure of 3. Our data revealed that the conformation of the nucleotide loop of 3 differs significantly in aqueous solution and in the crystalline state and indicated the presence of a specific H2O molecule `bound' via cooperative H‐bonds to three H‐bonding functionalities of the nucleotide loop. The observed conformational differences are attributed to structuring contributors to the nucleotide conformation that differ in solution and in the crystal. Most of these can be assigned to H2O molecules, whose position in the crystal is controlled, in part, by the specific crystal packing.

Kreiser, Wolfgang; Körner, Ferdinand

doi: 10.1002/(SICI)1522-2675(19991006)82:10<1610::AID-HLCA1610>3.0.CO;2-Tpmid: N/A

The structure of (+)‐β‐turmerone ((+)‐1a), a constituent of the rhizomes of Curcuma longa Linn., and Curcuma xanthorriza, is established as (1′R,6S)‐2‐methyl‐6‐(4′‐methylenecyclohex‐2′‐en‐1′‐yl)hept‐2‐en‐4‐one by synthesis of its enantiomer (−)‐1a, and of the corresponding (1′S,6S)‐diastereoisomer (+)‐1b as well. In a stereospecific seventeen‐step procedure, the monoterpene diols 2a and 2b of well‐established configuration are converted into the target compounds (−)‐1a and (+)‐1b, respectively. Moreover, (−)‐bisacurol (−)‐3a(II), the enantiomer of another bisabolane sesquiterpene derived from Curcuma xanthorriza, is obtained as a single stereoisomer and shown to be (1′S,6R)‐2‐methyl‐6‐(4′‐methylenecyclohex‐2′‐en‐1′‐yl)hept‐2‐en‐4‐ol, the relative configuration at the remaining OH‐substituted chiral center C(4) still being unknown.

Caron, Giulia; Ermondi, Giuseppe; Boschi, Donatella; Carrupt, Pierre‐Alain; Fruttero, Roberta; Testa, Bernard; Gasco, Alberto

doi: 10.1002/(SICI)1522-2675(19991006)82:10<1630::AID-HLCA1630>3.0.CO;2-Ppmid: N/A

Homologous N,N‐dimethyl‐phenylalkylamine oxides and N,N‐dimethyl‐diphenylalkylamine oxides were prepared. Their basicity and lipophilicity (octan‐1‐ol/H2O) were compared to those of the parent amines. In contrast to the amines, the basicity of all N,N‐dimethyl‐arylalkylamine oxides showed very limited pKa variations (range 4.65 – 5.01) with increasing chain length and number of Ph groups. The N‐oxides in their neutral form had a log PN value lower by 2.77±0.34 (n=9) units than that of the parent amine. The log PC of the cationic N,N‐dimethyl‐diphenylalkylamines was lower than that of their neutral form, with a decrement diff(log PN−C) that increased from 3.25 to 4.21 in the homologous series. Unexpectedly, the decrement diff(log PN−C) for the N‐oxides was much smaller than for the tertiary amines, being 0.23 for the aliphatic N,N‐dimethyl‐pentylamine oxide, 0.47±0.13 for the phenylalkylamine oxides, and 0.80±0.07 for the diphenylalkylamine oxides. In fact, the protonated N‐oxides had log PC values that were quite comparable to those of the protonated parent amines. Because of the differences in basicity, the difference in distribution coefficients at physiological pH (log D7.4) between a tertiary arylalkylamine and its N‐oxide was 0.82±0.66 (n=9). The pharmacokinetic implication is that N‐oxygenation may have a smaller effect on the urinary excretion of tertiary amines than usually assumed.

Seela, Frank; Becher, Georg

doi: 10.1002/(SICI)1522-2675(19991006)82:10<1640::AID-HLCA1640>3.0.CO;2-Npmid: N/A

Oligonucleotides containing 7‐substituted 8‐aza‐7‐deazaguanines (=6‐amino‐1,5‐dihydro‐4H‐pyrazolo[3,4‐d]pyrimidin‐4‐ones) were prepared by automated solid‐phase synthesis. A series of 7‐alkynylated 8‐aza‐7‐deaza‐2′‐deoxyguanosines (see 4a – d) were synthesized with the 7‐iodonucleoside 3c as starting material and by the Pd0/CuI‐catalyzed cross‐coupling reaction with various alkynes. Phosphoramidites were prepared from the 7‐substituted 8‐aza‐7‐deaza‐2′‐deoxyguanosine derivatives carrying halogeno, cyano, and hexynyl substituents. From the melting profiles of oligonucleotide duplexes, the Tm values as well as the thermodynamic data were determined. A significant duplex stabilization by the 7‐substituents was observed for the DNA⋅DNA duplexes, but not in the case of DNA⋅RNA hybrids.

Fráter, Georg; Müller, Urs; Kraft, Philip

doi: 10.1002/(SICI)1522-2675(19991006)82:10<1656::AID-HLCA1656>3.0.CO;2-Mpmid: N/A

The commercially important isochromane musk odorant Galaxolide® (=1,3,4,6,7,8‐hexahydro‐4,6,6,7,8,8‐hexamethylcyclopenta[g]‐2‐benzopyran; HHCB; 3) was separated into its diastereoisomers via the tricarbonyl(η6‐cyclopenta[g]‐2‐benzopyran)chromium complexes 10. Since GC/olfactometry indicated that only one enantiomer of each diastereoisomer (4RS,7RS)‐3 and (4RS,7SR)‐3 determines the odor characteristics of the commercial product, all four stereoisomers (4S,7R)‐, (4S,7S)‐, (4R,7S)‐, and (4R,7R)‐3 were synthesized by Friedel‐Crafts alkylation of 1,1,2,3,3‐pentamethylindane (11) with (S)‐ and (R)‐methyloxirane ((S)‐ and (R)‐12, resp.), acid‐catalyzed reaction of the resulting products with paraformaldehyde, and separation of the formed diastereoisomer pairs via the tricarbonyl(η6‐cyclopenta[g]‐2‐benzopyran)chromium complexes 10. The powerful musk odor of Galaxolide ® (3) was thus attributed to its (−)‐(4S)‐isomers (4S,7R)‐ and (4S,7S)‐3, while the (+)‐(4R)‐isomers (4R,7S)‐ and (4R,7R)‐3 were weak to almost odorless.

Riklin, Marianne; von Zelewsky, Alexander; Bashall, Alan; McPartlin, Mary; Baysal, Akin; Connor, Joseph A.; Wallis, John D.

doi: 10.1002/(SICI)1522-2675(19991006)82:10<1666::AID-HLCA1666>3.0.CO;2-Kpmid: N/A

The elusive chiral twisted alkene, 5,5′‐bi‐5H‐cyclopenta[2,1‐b : 3,4‐b′]dipyridinylidene, known also as 9,9′‐bi‐4,5‐diazafluorenylidene (BDAF), has been prepared in racemic form from 9‐bromo‐4,5‐diazafluorene and from 9,9′‐bi‐4,5‐diazafluorenyl and fully characterised. X‐Ray measurements show that there is a twist of 37.8° about the double bond between the 4,5‐diazafluorenylidene units. A 1 : 1 charge‐transfer compound with 7,7,8,8‐tetracyanoquinodimethane (TCNQ) contains an unusual packing arrangement which is centred around the formation of spiral stacks. Each BDAF molecule contributes one 4,5‐diazofluorenylidene unit to the backbone of the stack, while the second half is involved in hydrogen‐bonding interactions and additional stacking with TCNQ. Examples of complexes containing the axially symmetric tetradentate ligand binding to one and to two metal ions, [M(bdaf)Cl2] and [(MCl2)2(bdaf)] (M=Co, Ni, Zn), are reported.

Mancini, Ines; Guella, Graziano; Zibrowius, Helmut; Laurent, Dominique; Pietra, Francesco

doi: 10.1002/(SICI)1522-2675(19991006)82:10<1681::AID-HLCA1681>3.0.CO;2-9pmid: N/A

Massileunicellins A (7), B (9), and C (11) – which show a novel type of a second epoxy bridge in eunicellane diterpenes – were isolated from the gorgonian Eunicella cavoliniii collected near Marseille. Structural assignments are based on NMR and MS data of these compounds and of their ketal derivatives 8, 10, and 12. Negligible activity of the massileunicellins on L1210 and KB tumor cell lines, and similar results for related known compounds, cast doubt on high cytotoxicity reported for the latter by other authors.