bluuebunny/crossref_metadata_2025_split huggingface dataset:
Copper(II) complexes of potentially terdentate N2‐[(R)‐2‐hydroxypropyl]‐ and N2‐[(S)‐2‐hydroxypropyl]‐(S)‐phenylalaninamide for chiral recognition: Synthesis of the Ligands and Formation Constants
Authors: Dallavalle Francesco , Folesani Giuseppina , Bertuzzi Terenzio , Corradini Roberto , Marchelli Rosangela 
Published: December 2004

AbstractCopper(II) complexes of the ligands N2‐[(R)‐2‐hydroxypropyl]‐ and N2‐[(S)‐2‐hydroxypropyl]‐(S)‐phenylalaninamide performed chiral separation of N‐dansyl‐protected and unmodified amino acids in HPLC (reversed phase). With the aim of investigating which species are potentially involved in the discrimination mechanism, the two ligands were synthesized and their complexation equilibria with Cu2+ studied by potentiometry and spectrophotometry in aqueous solution up to pH 11.7. The formation constants of the species observed, [CuL]2+, [CuL2]2+, [CuLH–1]+, [CuL2H–1]+, [CuL2H–2], and [CuL2H–3]−, were quite similar for both compounds and were compared to those of (S)‐phenylalaninamide. Most probably, in [CuL2H–3]− the ligands behave as terdentate, with the deprotonated OH group occupying an apical position.
Dendrophanes: Water‐Soluble Dendritic Receptors. Preliminary communication
Authors: Mattei Sebastiano , Seiler Paul , Diederich FrançOis , Gramlich Volker 
Published: December 2004

AbstractThe dendritic cyclophanes (dendrophanes )1–3 containing a [6.1.6.1]paracyclophane as the initiator core embedded in dendritic poly(ether‐amide) shells of first (1), second (2), and third (3) generation were prepared and characterized. The X‐ray crystal‐structure analyses of esters 7 and 4, derivatives of cyclophane core 9 and first‐generation dendrophane 1, respectively, displayed open cavity binding sites suitable for the inclusion complexation of aromatic substrates. With their carboxylate surface groups, dendrophanes 1–3 were readily soluble in aqueous phosphate buffer (pH 8.0), and the complexation of naphthalene derivatives was investigated by 1H‐NMR and fluorescence titrations. The binding studies demonstrated that the cyclophane cavity remains open and accessible to appropriate substrates even at higher dendritic generations. The 1:1 complexes formed in aqueous buffer were of similar stability to those formed by the unbranched core 9 (Ka between 1000 and 10000 1 mol−1, 300 K). Investigations with the fluorescent probe 6‐(p‐toluidino)naphthalene‐2‐sulfonate (12) showed that the micropolarity at the dendrophane core decreases with increasing generation number.
Compounding Selectivity in Reactions of Diastereoisomeric Radical Intermediates. An experimental demonstration that the yield of a product from a diastereotopic‐group‐selective reaction can significantly exceed the level of group selectivity
Authors: Curran Dennis P. , Qi Hongyan 
Published: December 2004

AbstractReduction of a bis‐radical precursor, 6‐phenyl‐1,1‐bis[3‐(phenylselanyl)propyl]‐3a,4‐dihydro‐1H,3H‐cyclopenta[c]furan‐5‐one (6), with 3 equiv. of Ph3SnH provides mixtures of cis,cis‐ or cis,trans‐angular triquinane products (3aα,5aβ,8β,8aR*)‐ and (3aα,5aα,8β,8aR*)‐hexahydro‐3a‐propyl‐8‐phenyl‐5H‐dicyclopenta[b,c]furan‐7(8H)‐one (cis,cis‐12/cis,trans‐12), in yields that vary from 50%/50% to 91%/6% depending on the reaction concentration. A mechanistic model for this process is proposed that involves a non‐selective phenylselenium‐group abstraction step followed by successive kinetic resolutions of diastereoisomeric radical intermediates. This reaction shows how yields in group‐selective reactions can be compounded to levels above that ostensibly permitted by the level of the group‐selective step.
Regioselektive 1,3‐Dipolare Cycloadditionen eines ‘Thiocarbonyl‐methanids’ ((Alkylidensulfonio)methanids) mit aromatischen Sulfinen
Authors: Mlostoń Grzegorz , Linden Anthony , Heimgartner Heinz 
Published: December 2004

Regioselective 1,3‐Dipolar Cycloadditions of a ‘Thiocarbonyl‐methanide’ ((Alkylidenesulfonio)methanide) with Aromatic SulfinesReaction of the spirocyclic 2,5‐dihydro‐1,3,4‐thiadiazole 7 and thiobenzophenone S‐oxide (6a) in THF at 45° yielded the spirocyclic 1,3‐dithiolane 1‐oxide 8, thiirane 9, and the diazane derivative 10 in a ratio of 61:15:23 (Scheme 2). The formation of 8 is rationalized by a 1,3‐dipolar cycloaddition of ‘thiocarbonyl‐methanide’ 1, generated from 7 by thermal elimination of N2, and the CS bond of sulfine 6a. Cyclization of intermediate 1 leads to thiirane 9. Under the same conditions, 7 and adamantane‐2‐thione S‐oxide (6b) or 2,2,4,4‐tetramethyl‐3‐thioxocyclobutanone S‐oxide (4) reacted to give only 9 and 10 but no cycloadduct of type 8 (Scheme 4). With the aim to favor the formation of 8, a mixture of 6a and 1.1 equiv. of 7 was heated to 45° without any solvent in a sealed tube. The ratio of products was only slightly different from that of the thermolysis in THF. An analogous experiment with 7 and 9H‐fluorene‐9‐thione S‐oxide (6c) yielded cycloadduct 13 and 9 (Scheme 5). It is most interesting that the 1,3‐dipolar cycloadditions of 1 and the sulfines 6a and 6c proceeded with different regioselectivity. A reaction mechanism for the unexpected formation of 10 is proposed in Scheme 7. The key step is the base‐catalyzed ring opening of 7 and the nucleophilic addition of the thereby formed thiolate 21 onto the sulfonium ion 19.
Formation of Cyclic Ketals from Hydroxyalkyl Enol Ethers, a stereoelectronically controlled endo‐trig‐cyclization process
Authors: Deslongchamps Pierre , Dory Yves L. , Li Shigui 
Published: December 2004

AbstractAcid‐catalyzed cyclic ketal formation vs. hydrolysis of a series of hydroxyalkyl cyclic enol ethers in the presence of 1 equiv. of H2O, and acid‐catalyzed cyclic‐ketal formation (same ketals as above) vs. methanolysis of a series of mixed pent‐4‐enyl hydroxyalkyl ketals with N‐bromosuccinimide in the presence of 4 equiv. of MeOH led to the same result: the intramolecular cyclization processes occur at similar rates as the intermolecular H2O or MeOH attacks independently of the size of the rings formed (five‐, six‐, or seven‐membered), by cyclizations. These results can be explained by the facts that, due to stereoelectronic effects which impose a torsional strain to the sp2 hybridized O‐atom, the cyclization activation enthalpy decreases, as the length of the hydroxyalkyl chain increase (ease of cyclization: 7 > 6 > 5), whereas the entropy factor favors the cyclization in the reverse fashion (ease of cyclization: 5 > 6 > 7). The various reaction pathways have been examined using the semi‐empirical Hamiltonian AM1, and the results obtained confirm that large‐ring formation is enthalpically much favored over the cyclization processes leading to small rings (ease of cyclization: 7 > 6 > 5).
Enantioselektive Synthese von α‐Phosphinoketonen. Vorläufige Mitteilung
Authors: Enders Dieter , Berg Thorsten , Raabe Gerhard , Runsink Jan 
Published: December 2004

Enantioselective Synthesis of α‐PhosphinoketonesThe first asymmetric (CP)‐connective synthesis of α‐phosphinoketones in high enantiomeric purity (e.e.91–97%) is described. Key step is the highly diastereoselective phosphinylation of SAMP‐hydrazones (S)‐2 to produce α‐phosphinohydrazones (S,R)‐3, isolated as the more stable borane adducts. Subsequent ozonolysis afforded the title compounds (R)‐4, potential ligands for enantioselective homogeneous catalysis.
Total Synthesis of (+)‐Elacomine and (−)‐Isoelacomine, Two Hitherto Unnamed Oxindole Alkaloids from Elaeagnus commutata
Authors: Pellegrini Claudio , Weber Michael , Borschberg Hans‐Jürg 
Published: December 2004

AbstractRacemic elacomine ((±)‐2), a hemiterpene spiro oxindole alkaloid from Elaeagnus commutata, was synthesized in five steps from 6‐methoxytryptamine (19) in 16% overall yield (Scheme 3). The final oxidative rearrangement of the corresponding β‐carboline precursor (±)‐21 furnished isoelacomine ((±)‐22) as a by‐product (6% overall yield). A more elaborate route that started from L‐tryptophan furnished (+)‐2 and (−)‐22 with optical purities of 76% (Scheme 4) and established the absolute configuration of these compounds. A reinvestigation of the alkaloidal content of the roots of E. commutata showed that both elacomine and isoelacomine occur naturally in racemic form.
New Triterpene Saponins from Herniaria glabra
Authors: Freiler Michaela , Reznicek Gottfried , Jurenitsch Johann , Kubelka Wolfgang , Schmidt Wolfram , Schubert‐Zsilavecz Manfred , Haslinger Ernst , Reiner Josef 
Published: December 2004

AbstractThree new saponins 1–3 were isolated from Herniaria glabra by means of prep. HPLC and TLC. The structures were established mainly by a combination of 2D‐NMR techniques (COSY, TOCSY, ROESY, HMQC, and HMBC) as O‐α‐L‐rhamnopyranosyl‐(1→4)‐O‐β‐D‐glucopyranosyl‐(1‐→6)‐O‐[β‐D‐glucopyranosyl‐(1→2)]‐β‐D‐glucopyranosyl medicagen‐28‐ate (herniaria saponin 4; 1), O‐β‐D‐glucopyranosyl‐(1→3)‐O‐α‐L‐rhamnopyranosyl‐(1→2)‐O‐[β‐(3R)‐D‐apiofuranosyl‐(1→3)]‐β‐D‐4‐O‐acetylfucopyranosyl 3‐O‐(β‐D‐glucuronopyranosyl)‐16α‐hydroxymedicagen‐28‐ate (herniaria saponin 5; 2), and O‐α‐L‐rhamnopyranosyl‐(1→4)‐O‐β‐D‐glucopyranosyl‐(1→6)‐O‐[β‐D‐6‐O‐acetylglucopyra nosyl‐(1→2)]‐β‐D‐glucopyranosyl medicagen‐28‐ate (herniaria saponin 6; 3).
Nucleotides. Part XLVI. The synthesis of phospholipid conjugates of antivirally active nucleosides by the improved phosphoramidite methodology
Authors: Sigmund Harald , Pfleiderer Wolfgang 
Published: December 2004

AbstractThe application of the improved phosphoramidite strategy for the synthese of oligonucleotides using β‐eliminating protecting groups to phospholipid chemistry offers the possibility to synthesize phospholipid conjugates of AZT (6) and cordycepin. The synthesis of 3′‐azido‐3′‐deoxythymidine (6) was achieved by a new isolation procedure without chromatographic purification steps in an overall yield of 50%. Protected cordycepin ( = 3′‐de‐oxyadenosine) derivatives, the N6,2′‐bis[2‐(4‐nitrophenyl)ethoxycarbonyl]cordycepin (12) and the N6,5′‐bis[2‐(4‐nitrophenyl)ethoxycarbonyl]cordycepin (13) wre prepared by known methods and direct acylation of N6‐[2‐(4‐nitrophenyl)ethoxycarbonyl]cordycepin (9), respectively. These protected nucleosides and the 3′‐azido‐3′‐de‐oxythymidine (6) reacted with newly synthesized and properly characterized lipid‐phosphoramidites 21–25, catalyzed by 1H‐tetrazole, to the corresponding nucleoside‐phospholipid conjugates 26–38 in high yield. The deprotection was accomplished via β‐elimination with 1,8‐diazabicyclo[5.4.0]undec‐7‐ene (DBU) in aprotic solvents to give analytically pure nucleoside‐phospholipid diesters 39–51 as triethylammonium or sodium salts. The newly synthesized compounds were characterized by elemental analyses and UV and 1H‐NMR spectra.
Synthesis of Tenuilobine, a Bis‐polyamine Alkaloid from Oncinotis tenuiloba, and Its Transamidation to Isotenuilobine
Authors: Doll Martin K.‐H. , Guggisberg Armin , Hesse Manfred 
Published: December 2004

AbstractFrom the leaves of Oncinotis tenuiloba STAPF, a novel polyamine alkaloid, tenuilobine (9), was isolated. This paper presents the synthesis of 9, as well as the base‐catalyzed Zip reaction of 9, leading to the transamidation product isotenuilobine (10). The structure of 10 was further confirmed by 2D‐NMR correlation spectroscopy. For analytical purposes, the bis‐polyamines 9 and 10 were converted into their pentaacetyl derivatives 12 and 11, respectively, which were readily separable by reverse‐phase HPLC.
Further C‐Alkylations of Cyclotetrapeptides via Lithium and Phosphazenium (P4) Enolates: Discovery of a New Conformation
Authors: Seebach Dieter , Bezençon Olivier , Jaun Bernhard , Pietzonka Thomas , Matthews Jennifer L. , Kühnle Florian N. M. , Schweizer W. Bernd 
Published: December 2004

AbstractFour cyclotetrapeptides containing one (1, 2) or two (3, 4) chiral amino acids have been C‐alkylated or C‐hydroxyalkylated through Li+ or phosphazenium (P4 · H+) enolates. The reactions are completely diastereoselective (by NMR or HPLC analysis) with respect to the newly formed backbone stereogenic centres (Tables 2 and 3). The reactivity of the polylithiated species responsible for these alkylations is such that only highly reactive electrophiles (MeI, BnBr, primary allylic halides, aldehydes, CO2) can be employed. It is shown that the position, and thus the chirality sense, of the newly formed stereogenic centre in a given cyclotetrapeptide backbone is controlled by the positioning of N‐methyl groups in the starting material (cf. cyclo(‐MeLeu‐Gly‐D‐Ala‐Sar‐) (3) and cyclo(‐Leu‐Sar‐MeDAla‐Gly‐) (4) in Scheme 1). With Schwesinger's phosphazene P4‐base, all NH groups are first benzylated and C‐benzylation then takes place at a sarcosine, rather than an N‐benzylglycine residue (Table 3). In contrast to open‐chain N‐benzyl peptides, the N‐benzylated cyclotetrapeptides could not be debenzylated under dissolving‐metal conditions (Na/NH3). Conformational analysis (NMR spectroscopy and X‐ray diffraction) shows that the prevailing species have cis/trans/cis/trans(ctct) peptide bonds (zigzag conformation of Ci backbone symmetry, Figs. 2–4). However, a hitherto unknown conformation of cyclotetrapeptides has been found in CDCl3 solutions of the hydroxyalkylated products 18–21 (obtained with EtCHO and PhCHO as electrophiles; Fig.4). The new conformation has four trans peptide bonds and is believed to result mainly from intramolecular H‐bond formation, involving the newly generated alkyl‐ or arylserine residue. This assumption has also been supported by modelling (TRIPOS force field, SYBYL, see Fig.5 and Table 6). The structure may be considered as a β‐turn mimic.
Nucleotides. Part IL. Synthesis and Characterization of Cordycepin‐Trimer‐Vitamin and ‐Lipid Conjugates Potential Inhibitors of HIV‐1 Replication
Authors: Wasner Marita , Pfleiderer Wolfgang , Suhadolnik Robert J. , Horvath Susan E. , Kon Ning , Guan Ming‐Xu , Henderson Earl E. , Adelson Martin E. , Henderson Earl E. , Suhadolnik Robert J. 
Published: December 2004

AbstractThe syntheses of biodegradable 2′‐ and 5′ ‐ester and 2′‐ and 5′ ‐carbonate conjugates of the antivirally active 3′‐deoxyadenylyl‐(2′–5′)‐3′‐deoxyadenylyl‐(2′–5′)‐3′‐deoxyadenosine (cordycepin‐trimer core) with the vitamins, E, D2, and A and the lipids 1,2‐di‐O‐palmitoylglycerol and 1,2‐di‐O‐hexadecylglycerol were achieved first by preparation of the trimeric educts 19–21 (Scheme 1). Secondly, these substances were condensed with the lipophilic residues via a succinate or carbonate linker and then deprotected by β‐elimination of the npeoc and npe protecting groups and acid treatment for detritylation without harming the ester and carbonate functions, respectively (Scheme 2). Metabolically stable cordycepin‐trimer‐vitamin and ‐lipid conjugates are a new class of bioconjugates that inhibit HIV‐1‐induced syncytia formation with IC50 values of 7, 18, and 24 m̈M for 39, 29, and 42, respectively, and inhibit HIV‐1 reverse transcriptase (RT) activity from 14 to 96% (see Table). Of the nine conjugates tested, inhibition of HIV‐1 replication by 28, 29, 32, 40, and 42 may be attributed in part to the activation of the RNase L/PKR antiviral pathways. Trimer conjugate 42 showed the greatest inhibition of HIV‐1 replication, i.e., a 120‐fold decrease in HIV‐1‐induced syncytia formation and an 88% inhibition of HIV‐1 reverse transcriptase (RT). This inhibition of replication of HIV‐1 by 42 can be attributed in part to the activation of recombinant, human RNase L. The inhibition of HIV‐1 replication by the cordycepin‐trimer‐vitamin and ‐lipid conjugates is significantly greater than that observed for the (2′–5′) A‐trimer core or cordycepin‐trimer core.
1,1,2,2‐Tetraethynylethanes: Synthons for Tetraethynylethenes and Modules for Acetylenic Molecular Scaffolding
Authors: Tykwinski Rik R. , Diederich François , Seiler Paul , Gramlich Volker 
Published: December 2004

AbstractThe synthesis of functionalized 1,1,2,2‐tetraethynylethanes (= 3,4‐diethynylhexa‐1,5‐diynes) as synthons for tetraethynylethenes (3,4‐diethynylhex‐3‐ene‐1,5‐diynes) and as building blocks for three‐dimensional acetylenic molecular scaffolding targeting the synthesis of the molecular carbon belts 3 and 4 is reported (Scheme 1). Reaction of diethyl oxalate and (trialkylsilyl)ethynyl Grignard reagents afforded the silyl‐protected 3,4‐diethynylhexa‐1,5‐diyne‐3,4‐ diols 7 and 8 which were transformed in high yields into the cyclic carbonate 9 and the cyclic orthoesters 10–13, respectively (Scheme 2). The solid‐state structures of 9 and 10 were elucidated by X‐ray crystallography. The alkyne protecting groups in 9, 10, and 12 were smoothly removed to give the free tetraynes 14–16 as relatively stable oils in nearly quantitative yields (Scheme 3). Orthoesters 15 and 16 underwent Pd‐catalyzed cross‐coupling with iodobenzene to give the tetraphenyl derivatives 17 and 18 (Scheme 4). Thermal acid‐catalyzed elimination of the orthoester moieties in 12 and 13 produced the silyl‐protected tetraethynylethenes 19 and 20 and concluded a novel, simple three‐step synthesis of these fully two‐dimensionally conjugated π‐chromophores (Scheme 5).
Synthesis of Carbocyclic C‐Nucleosides Containing Nonnatural Pyrimidine Bases
Authors: Hildbrand Stefan , Leumann Christian , Scheffold Rolf 
Published: December 2004

AbstractA series of new carbocyclic C‐nucleosides with a cis‐4′‐(hydroxymethyl)cyclopent‐2′‐enyl sugar moiety and unnatural pyrimidine bases (2–6) were synthesized in racemic form in two steps starting from the easily accessible cyclic carbonate 1.
Isotactic and Atactic Copolymerization of Styrene and Carbon Monoxide Using Cationic Palladium‐Phosphino(dihydrooxazole) Complexes. Preliminary Communication
Authors: Sperrle Martin , Aeby Anton , Consiglio Giambattista , Pfaltz Andreas 
Published: December 2004

AbstractCationic palladium complexes 2 containing coordinated phosphino(dihydrooxazole) ligands 1 give catalytic systems which allow the production of alternating styrene‐carbon monoxide copolymers. Depending on the symmetry of the ligand, the copolymers are produced either with a highly isotactic or with an essentially completely atactic microstructure. Termination of the polymeric chain is mainly due to a β‐H‐elimination reaction. Both linear ((E)‐PhCHCHCO) and branched (CH2C(Ph)CO) unsaturated end groups were identified.
Reisolation of Carotenoid 3,6‐Epoxides from Red Paprika (Capsicum annuum)
Authors: Deli József , Molnár Péter , Matus Zoltán , Tóth Gyula , Steck Andrea 
Published: December 2004

AbstractCucurbitaxanthin A (= (3S,5R,6R,3′R)‐3,6‐epoxy‐5,6‐dihydro‐β,β‐ carotene‐5,3′‐diol; 5), cucurbitaxanthin B (= (3S,5R,6R,3′S,5′R,6′S)‐3,6,5′, 6′‐diepoxy‐5,6,5′,6′‐tetrahydro‐β,β‐carotene‐5,3′‐diol; 6), the epimeric cucurbitachromes 1 and 2 (= (3S,5R,6R,3′S,5′R,8′S)‐ and (3S,5R,6R,3′S,5′R,8′R)‐3,6,5′, 8′‐diepoxy‐5,6,5′,6′‐tetrahydro‐β,β‐carotene‐5,3′‐diol, resp.; 9/10), cycloviolaxanthin (= (3S,5R,6R,3′S,5′R,6′R)‐3,6,3′, 6′‐diepoxy‐5,6,5′,6′‐tetrahydro‐β,κs‐carotene‐5,5′‐diol; 8), and capsanthin 3,6‐epoxide (= (3S,5R,6R,3′S,5′R)‐3,6‐epoxy‐5,6‐dihydro −5,3′‐dihydroxy‐β,κ‐caroten‐6′‐one; 7) were isolated from red spice paprika (Capsicum annuum var. longum) and characterized by their 1H‐ and 13C‐NMR, mass, and CD spectra.
An Unexpectedly Stable Chiral Hydrido‐Solvent Complex of RuII: A mechanistic link in the enantioselective hydrogenation of pyrones. Preliminary communication
Authors: Currao Antonio , Feiken Nantko , Macchioni Alceo , Nesper Reinhard , Pregosin Paul S. , Trabesinger Gerald 
Published: December 2004

AbstractThe ligand (6,6′‐dimethoxybiphenyl‐2,2′‐diyl)bis[3,5‐di(tert‐butyl)phenylphosphine] (1) forms an unexpectedly stable hydrido‐bis‐solvento complex of composition [RuH(isopropanol)2(1)]BF4, (2) under the conditions used in the enantioselective hydrogenation of pyrones. The structure of 2, determined by X‐ray diffraction, represents the first well‐characterized chiral five‐coordinate bis‐phosphine ruthenium‐hydride complex stable as a solvento complex, and provides a structural link in the enantioselective pyrone hydrogenation cycle catalyzed by [Ru(OAc)2(1)]. Using the arene complex [RuH(p‐cymene)(1)]BF4 (3), the chiral pocket of coordinated 1 is shown to be relatively rigid, via NMR spectroscopy. This is reflected in restricted rotation about one of the four P–[3,5‐di(tert‐butyl)phenyl] PCipso bonds at room temperature.
Detection of Noncovalent Complexes of Hydroxamic‐Acid Derivatives by means of electrospray mass spectrometry
Authors: Bigler Laurent , Baumeler Andreas , Werner Christa , Hesse Manfred 
Published: December 2004

AbstractThe complexes of isolated benzoxazinone derivatives with FeIII were investigated by means of electrospray ionization mass spectrometry. The hydroxamic‐acid derivatives could be differentiated from the lactam or the methyl‐hydroxamate derivatives by the formation of FeIII complexes with two or three ligands. These complexes or adducts of them have been identified in the mass spectra. Moreover, the mass‐spectral behavior of these complexes was not markedly influenced by the presence of a β‐D‐glucopyranosyloxy substituent.
Carbenoid Reactions of Dimethyl Diazomalonate with Aromatic Thioketones and 1,3‐Thiazole‐5(4H)‐thiones
Authors: Mlostón Grzegorz , Heimgartner Heinz 
Published: December 2004

AbstractDimethyl diazomalonate (4) and thiobenzophenone (2a) do not react in toluene even after warming to 50°. After addition of catalytic amounts of Rh2(OAc)4, a smooth reaction under N2 evolution afforded a mixture of thiiranedicarboxylate 5 and (diphenylmethylidene)malonate 6 (Scheme 2). A reaction mechanism via an intermediate ‘thiocarbonyl ylide’ 7, formed by the addition of the carbenoid species 8 to the S‐atom of 2a, is plausible. Similar reactions were carried out with 9H‐xanthene‐9‐thione (2b), 9H‐thioxanthene‐9‐thione (2c, Scheme 4), and 1,3‐thiazole‐5(4H)‐thione 18 (Scheme 6). In the cases of 2b and 2c, spirocyclic 1,3‐dithiolanetetracarboxylates 14a and 14b, respectively, were obtained as the third product. Reaction mechanisms for their formation are proposed in Scheme 5: S‐transfer from intermediate thiirane 12 to the carbenoid species yielded thioxomalonate 15 which underwent a 1,3‐dipolar cycloaddition with ‘thiocarbonyl ylide’ 16. An alternative is the formation of ‘thiocarbonyl ylide’ 17 via carbene addition to 15, followed by 1,3‐dipolar cycloaddition with 2b and 2c, respectively.
Protein‐Loop Mimetics: A Diketopiperazine‐Based Template to Stabilize Loop Conformations in Cyclic Peptides Containing the NPNA and RGD Motifs
Authors: Bisang Christian , Weber Christoph , Robinson John A. 
Published: December 2004

AbstractWe explore here an approach to mimic the structures and biological functions of protein loops in small synthetic molecules, by grafting the loop of interest onto an organic template comprising a bicyclic diketopiperazine, prepared by the formal coupling of (2S,4S)‐4‐aminoproline (Pro(NH2)) and aspartic acid (Asp). The Fmoc‐protected template 4 is used to prepare cyclo(‐Ala1‐Asn2‐Pro3‐Asn4‐Ala5‐ Ala6‐Temp‐) (5) and cyclo(‐Ala1‐Arg2‐Gly3‐Asp4‐Temp‐) (6) (where Temp = template derived from 4), containing the Asn‐Pro‐Asn‐Ala (NPNA) and Arg‐Gly‐Asp (RGD) motifs. The conformational properties of these molecules are studied in aqueous solution by NMR and simulated‐annealing methods. The NPNA motif, an immunodominant epitope on the circumsporozoite surface protein of the malaria parasite Plasmodium falciparum, is shown to adopt a stable type‐I β‐turn in 5. The template in 5 adopts a preferred conformation with Pro(NH2)χ1 ≈︁ −35° and the Asp moiety χ1 ≈︁ 70°. A different template conformation is inferred for 6, with Pro(NH2)χ1 ≈︁ 0°, but the ARGD loop appears by NMR to undergo rapid conformational averaging. Solid‐phase binding assays reveal that 6 displays modest antagonist activity towards both the integrin αIIbβ3 and αvβ3 receptors.