l-Proline induced self-assembly of indolicidin derived palindromic tripeptide

We describe the synthesis, crystal structure, and various microscopic studies of the palindromic tripeptide WPW derived from antimicrobial peptide indolicidin. The present study reveals that tripeptide 1 and 2 undergo self-assembly to form vesicular structures after prolonged incubation, thus giving an interesting insight into the contribution of l-proline and flanking tryptophan residues in the self-assembly process. These vesicles were also amenable to simple focused ion beam (FIB)-aided bisection and thus possible to mill these vesicles to create different shapes. The circular dichroism (CD) analysis indicates that incubation promotes and stabilizes the more favorable secondary structures for 1 and 2. Preliminary result shows that tripeptide 1 exhibits appreciable interaction with Tb³⁺ as determined by quenching in tryptophan fluorescence.     

Synthesis of l-azaisotryptophan and its analogs: a general access to new 2-substituted azaindoles

l-(N-Cbz)-7-azaisotryptophan, l-(N-Cbz)-1a, a new isostere of tryptophan, was synthesized by reacting Li₂-(N-Boc)-2-amino-3-picoline, Li₂-(N-Boc)-2a, with appropriately protected l-aspartic acid followed by simple functional group manipulation. This synthetic success led us to access a set of analogs of azaisotryptophan (4a–c; 6a–c) as well as a new class of chiral amines (7a–c; 8a–c) for future application in asymmetric synthesis and design of homochiral ligands. Further, we have generalized the method substantiating a variety of new azaindol-2-yl derivatives (10aa–10lc) with functionalized substituents. In a preliminary luminescence characterization, l-(N-Cbz)-1a has exhibited about 30 nm bathochromic shifted fluorescence emission compared to tryptophan and (N-Cbz)-tryptophan.     

Slipping of a histidine improved the peroxidase activity of a de novo designed polypeptide packing an iron porphyrin

Polypeptides with two histidines and an iron porphyrin (1H⁴⁰-7H⁴⁶) were synthesized with a variety of positions of a histidine. In 4H⁴³, histidine (H⁴³) was in the hydrophobic region of an α-helix. The other polypeptides were of slightly or substantially distorted conformation. In the pH 7.2 buffer solution, two histidines of the polypeptide coordinated the iron porphyrin regardless of their positions. Some polypeptides (1H⁴⁰, 3H⁴², and 5H⁴⁴) showed an enhanced catalytic activity in the peroxidase reaction using cumene hydroperoxide compared to that of 4H⁴³, whereas some polypeptides (2H⁴¹ and 6H⁴⁵) were ineffective catalysts. The distortion of the peptide conformation by the addition of MeOH was also effective for the peroxidase reaction.     

Photoinduced cycloadditions of N-methyl-1,8-naphthalenedicarboximides with alkynes

Photoinduced cycloadditions of N-methyl-1,8-naphthalenedicarboximide 1 with phenylacetylenes 2a-2c, cyclopropylacetylene 2d, diphenylacetylenes 2e-2f and 1-phenylpropyne 2g were investigated. In the case of phenylacetylenes 2a, 2b and cyclopropylacetylene 2c, photoreaction with 1 takes place at the naphthalene C(1)C(2) bond to give the cyclobutene products. For 4-methoxyphenylacetylene 1c, the cyclobutene 3c is obtained together with the 4-benzo[a]thebenidinone 4c derived from a primary oxetene product formed by [2+2] addition of the imide carbonyl with the alkyne. Similar to 2c, photocycloaddition of 1 with 2e and 2f gave the cyclobutenes 7e, 7f, 8f and the 4-benzo[a]thebenidinone products 9e, 9f and 10f, respectively, derived from the corresponding oxetenes. Photoreaction of 1 with 2g gave cyclobutene 7g and benzo[a]thebenidinone 9g. Sensitization experiment and internal heavy atom effect study showed that these reactions proceed from the ππ* singlet excited state of 1. Estimation of the free energy change for electron transfer between ¹1* and the alkynes and the calculation of charge and spin density distribution in the anion radical of 1 and the cation radical of the alkynes suggested that the cyclobutene products are formed by direct [2+2] cycloaddition of ¹1* with the alkyne, while the formation of the oxetene products is the result of electron transfer interaction between ¹1* and the alkyne. The regioselectivity in the oxetene formation is accounted for by charge and spin density distribution in the anion radical of 1 and the cation radical of the alkyne.     

Osmium assisted C-H activation and CN cleavage of N-(2′-hydroxyphenyl) benzaldimines. Synthesis, structure and electrochemical properties of some organoosmium complexes

Reaction of N-(2′-hydroxyphenyl)-4-R-benzaldimines (L-R, R = OCH₃, CH₃, H, Cl and NO₂) with [Os(PPh₃)₃Br₂] in refluxing 2-methoxyethanol in the presence of triethylamine affords two families of organoosmium complexes (1-R and 2-R). In both 1-R and 2-R complexes a benzaldimine ligand is coordinated to the metal center as tridentate C,N,O-donor. In the 1-R complexes, a bidentate N,O-donor imionsemiquinonate ligand, derived from the hydrolysis of another benzaldimine, and a PPh₃ ligand are also coordinated to osmium. In the 2-R complexes, a carbonyl, derived from decarbonylation of 4-R-benzaldehyde (derived from the same hydrolysis stated above), and two PPh₃ ligands take up the remaining coordination sites on osmium. Structures of the 1-Cl and 2-OCH₃ complexes have been determined by X-ray crystallography. All the 1-R and 2-R complexes are diamagnetic, and show characteristic ¹H NMR signals and intense MLCT transitions in the visible region. Cyclic voltammetry on the 1-R complexes shows a reversible Os(III)-Os(IV) oxidation within 0.47-0.67 V (vs SCE), followed by an irreversible oxidation of the imionsemiquinonate ligand within 1.10-1.36 V. An irreversible Os(III)-Os(II) reduction is also displayed by the 1-R complexes within −1.02 to −1.14 V. Cyclic voltammetry on the 2-R complexes shows a reversible Os(II)-Os(III) oxidation within 0.29-0.51 V, followed by a quasi-reversible oxidation within 1.04-1.29 V, and an irreversible reduction of the coordinated benzaldimine ligand within −1.16 to −1.31 V.     

Preparation of glycoluril monomers for expanded cucurbit[n]uril synthesis

Glycoluril derivatives bearing free ureidyl groups (1) and bis(cyclic ethers) (2) are the fundamental building blocks for the synthesis of cucurbituril, its derivatives, and its congeners. The known derivatives of 1 and 2 fall into two main classes—those bearing alkyl or aryl functional groups on their convex face. In this paper we present a third class of glycolurils, namely those bearing substituents that are electron withdrawing in character. This class of compounds carries carboxylic acid derived functional groups on their convex face and are derived from diesters 1e and 2e. An improved synthesis of 1e and 2e is reported and their modification described. For example, 1e and 2e are converted into secondary amides (10-15) by heating in solutions of the neat primary amines. The secondary amides can be transformed into imides (19-22, 24, 25) by heating with PTSA in ClCH₂CH₂Cl. The isolation of these compounds in pure form in high yields is accomplished by simple and scalable washing or recrystallization procedures. We also present the X-ray crystallographic characterization of bis(cyclic ethers) 2e, 8, and 22. We anticipate that the ready availability of ester, carboxylate, acid, secondary amide, imide, and tertiary amide derivatives of 1 and 2 will expand the scope of the synthesis of cucurbituril derivatives by providing a new class of building blocks with electron withdrawing substituents.     

A synthesis of a common intermediate to the lactone-pyrrolidinone ring systems in oxazolomycin A and neooxazolomycin

A 5-exo-dig radical cyclisation of the bromoamide 34 derived from the enantiopure α-ethynyl substituted amino alcohol 31 led to a 2:1 mixture of β-C3 and α-C3 methyl epimers of the pyrrolidinone 35a-36a in a combined yield of 73%. Treatment of the homoallylic alcohol 35b, derived from 35a, with OsO₄-TMEDA, gave a single diastereoisomer of the pyrrolidinone triol 37, resulting from selective dihydroxylation from the β-face, i.e. syn to the CH₂OH group of 35b. The pyrrolidinone triol 37 is a potential common precursor, cf. 9, to the spiro β-lactone pyrrolidinone 8 and the γ-lactone pyrrolidinone 10 ring systems in oxazolomycin A (1) and neooxazolomycin 2, respectively. Sequential protection of the 1,2-diol functionality in 37 as the acetonide 39, and the primary alcohol group in 39 as the SEM ether 41a, followed by methylation of the nitrogen centre in 41a, using NaH-MeI, then gave the selectively protected pyrrolidinone 42.     

Marine bacterial inhibitors from the sponge-derived fungus Aspergillus sp.

Chromatographic separation of a crude extract obtained from the fungus Aspergillus sp., isolated from the Mediterranean sponge Tethya aurantium, yielded a new tryptophan derived alkaloid, 3-((1-hydroxy-3-(2-methylbut-3-en-2-yl)-2-oxoindolin-3-yl)methyl)-1-methyl-3,4-dihydrobenzo[e][1,4]diazepine-2,5-dione (1), and a new meroterpenoid, austalide R (2), together with three known compounds (3–5). The structures of the new compounds were unambiguously elucidated on the basis of extensive one and two-dimensional NMR (¹H, ¹³C, COSY, HMBC, and ROESY) and mass spectral analysis. Interestingly, the compounds exhibited antibacterial activity when tested against a panel of marine bacteria, with 1 selectively inhibiting Vibrio species and 2 showing a broad spectrum of activity. In contrast, no significant activity was observed against terrestrial bacterial strains and the murine cancer cell line L5178Y.     

Columnar/smectic metallomesogens derived from heterocyclic benzoxazoles

The synthesis, mesomorphic behavior, and optical properties of two new series of metal complexes 1a,b-M (M=Pd, Cu, Zn) derived from benzoxazoles 2a,b are reported. The crystal and molecular structures of mesogenic 5-decyloxy-2-(6-decyloxybenzooxazol-2-yl)phenol and nonmesogenic bis[5-octyloxy-2-(6-octyloxybenzooxazol-2-yl) phenol]Pd(II) were determined by means of X-ray structural analysis. Two benzoxazoles 2a exhibited monotropic SmA phases, and all benzoxazoles 2b were nonmesogenic. On the other hand, metal complexes 1a-M exhibited distinctly different mesomorphism from complexes 1b-M. Complexes 1a-Pd formed SmC phases; complexes 1a-Cu and 1a-Zn formed crystal phases. In contrast, complexes 1b-Zn exhibited columnar phases, and complexes 1b-Cu and 1b-Pd were nonmesogenic. The difference of the mesomorphism in 1a-M and 1b-M was probably attributed to the geometry and/or the overall molecular shape created by 2a and 2b. The electronic configuration of metal ion might play an important role in forming the mesophases. The fluorescent properties of these compounds were also examined.     

Studies on the Synthesis of Reidispongiolide A: Stereoselective Synthesis of the C(22)-C(36) Fragment

A highly stereoselective synthesis of the C(22)-C(36) fragment 2 of reidispongiolide A is described. This synthesis features the highly stereoselective mismatched double asymmetric crotylboration reaction of the aldehyde derived from 5 and the new chiral reagent (S)-(E)-7 that provides 12 with >15:1 dr. Subsequent coupling of the derived vinyl iodide 3 with aldehyde 16 provided allylic alcohol 17, that was elaborated by three steps into the targeted reidispongiolide fragment 2.     

A substrate controlled, very highly diastereoselective Morita-Baylis-Hillman reaction: a remote activation of the diastereofacial selectivity in the synthesis of C-3-branched deoxysugars

The Morita-Baylis-Hillman (MBH) reaction of p-nitrobenzaldehyde with C (6) acyl protected enuloside 1 in the presence of TiCl₄/TBAI yielded highly diastereoenriched C-3-branched deoxysugar derivative or MBH adduct 1′a in high yield, while reactions of unprotected enuloside 2a and C (6) alkyl protected enulosides 2d-e with p-nitrobenzaldehyde under the same conditions afforded the adducts 2′a and 2′d-e, respectively, in low yield with moderate selectivity. Several representative aromatic and aliphatic aldehydes were selected to undergo MBH reaction with 1 to give their respective adducts in very good yield with a very high diastereoselectivity. A plausible mechanism based on the assumption of a Zimmerman-Traxler-type transition state was proposed to explain the excellent selectivity observed with adducts derived from 1. The synthetic application of these adducts were shown by their stereoselective reduction to corresponding threo isomers in very good yield.     

Cocrystals of U-shaped ureadicarboxylic acid with 2-aminopyrimidine and melamine: rhombus-shaped cyclic heterotetramer motifs

Single crystal X-ray structures of cocrystals, 1·2 and 1·3, derived from U-shaped ureadicarboxylic acid (1) with 2-aminopyrimidine (2) and melamine (3), respectively, were examined. Cocrystals were obtained as a 1:1 mixture of 1 and the corresponding base. Two molecules of 1 and two molecules of the base were combined together via intermolecular H-bonding creating a supramolecularly assembled cyclic heterotetramer motif of rhombus shape. In the case of cocrystal 1·3, the cyclic heterotetramers were connected via H-bonding by utilizing a remaining amino group of melamine resulting in the formation of a tape of cyclic heterotetramer.     

A general method for the synthesis of the most powerful naturally occurring Maillard flavors

The natural flavors 2-acetyl-1-pyrroline 1a, 2-propionyl-1-pyrroline 1b, 2-acetyl-3,4,5,6-tetrahydropyridine 1c, 2-acetyl-2-thiazoline 1d, 2-propionyl-2-thiazoline 1e, and the artificial flavor 2-acetyl-5,6-dihydro-4H-1,3-thiazine 1f have been prepared by catalytic SeO₂ oxidation of the corresponding cyclic imines 6a-c and sulfur cyclic imines 7a-c using TBHP as co-oxidant. The oxidation of the pyrrolines 1a and b is completely regioselective. Professional olfactory evaluation together with the odor threshold of the new flavor 1f is reported.     

Electrochemical synthesis of 5,6-dihydroxy-2-methyl-1-benzofuran-3-carboxylate derivatives

Electrochemical oxidation of catechols (1a-c) has been studied in the presence of methyl acetoacetate (2a) and ethyl acetoacetate (2b) as nucleophiles in aqueous solution using cyclic voltammetry and controlled-potential coulometry. The results indicate that the quinones derived from catechols (1a-c) participate in Michael addition reactions with 2a and 2b to form the corresponding benzofuran derivatives (3a-f). The electrochemical synthesis of 3a-f has been successfully performed in an undivided cell in good yield and purity. The oxidation mechanism was deduced from voltammetric data and by coulometry at controlled potential. The products have been characterized after purification by IR, ¹H NMR, ¹³C NMR, MS, and single crystal X-ray diffraction.     

Exceptional molecular architectures via cycloadditions to pyrenequinones

The thermal reaction of phencyclone (2) with a 1:1 mixture of 1,8-pyrenequinone (4) and 1,6-pyrenequinone (5) yields 2:1 adducts only of compounds 2 and 4. The observed polycyclic aromatic hydrocarbon 8 is formed via double Diels-Alder addition of 2 to 4, and the polycyclic ketone 9 arises from a combination of Diels-Alder and hetero-Diels-Alder reactions of 2 and 4. In contrast, Lewis acid-catalyzed reactions of 2, 4, and 5 give 2:1 adducts only of 2 and 5. The chief product, polycyclic diketone 10, is derived from a double hetero-Diels-Alder addition of 2 to 5. X-ray analysis of compound 8 shows it to be an exceptionally large polycyclic aromatic arch, and the X-ray structure of 10 reveals it to be a chiral molecular tweezer.     

Synthesis of the spiroacetal fragment of broussonetine H

(2S,6S)-2-(3-Bromopropyl)-1,7-dioxaspiro[5.5]undecane 3 was prepared by the addition of the acetylide derived from (4S)-4-benzyloxy-7-tert-butyldiphenylsilyloxyhep-1-yne 8 to δ-valerolactone 6 followed by treatment with hydrogen and palladium on charcoal which effected hydrogenation of the alkyne, hydrogenolysis of the benzyl ether and subsequent spiroacetal formation. The (4S)-stereochemistry in acetylene 8 was established by addition of trimethylsilylacetylene 10 to (2S)-epoxide 9, which in turn is derived from l-glutamic acid 11.     

An efficient synthesis of benzofurans and their application in the preparation of natural products of the genus Calea

The intramolecular cyclization of the β-substituted olefins methyl 2-aryloxy-3-dimethylaminopropenoates 3a-3f catalyzed by Lewis acids leads to a short and novel synthesis of benzofurans 2a-2f. When the olefins 4-dimethylamino-3-aryloxy-3-buten-2-ones 4a-4f were used, the cyclization process was faster and provided the corresponding substituted 2-acetylbenzofurans 1a-1f. Among the latter, naturally occurring compounds calebertin (1a), caleprunin A (1b), and caleprunin B (1c) were prepared in good overall yields. These benzofurans were also obtained by direct treatment under MW irradiation of the precursors 1-aryloxypropan-2-ones 7a-7c with DMFDMA, followed by addition of the catalyst, resulting in a route that was one step shorter.     

Imino Diels-Alder reaction of boronates. Preparation and characterization of new 3,4-dihydroquinoline and 1,2,3,6-tetrahydropyridine derivatives

The preparation of 3,4-dihydroquinolines (2a-d and 3a,b,d), as well as 1,2,3,6-tetrahydropyridines (4a-e) by imino Diels-Alder reaction of boronates (1a-e) with 2,3-dimethylbutadiene is reported. Boronates (1a-d) containing substituents meta and para relative to the imino fragment lead to diastereomeric mixtures of 4-methyl-4-ethenyl-3,4-dihydroquinolines (2, 3) and tetrahydropyridines (4). In contrast, the presence of an electron withdrawing substituent at the para position (1e), favors the iminodienophile behavior giving 4,5-dimethyl-1,2,3,6-tetrahydropyridine (4e) as the main product. The results show that boronates derived from Schiff bases are electron deficient species which can act either as dienophiles or dienes in the reaction with 2,3-dimethylbutadiene to give 3,4-dihydroquinolines and 1,2,3,6-tetrahydropyridines. All products were characterized by NMR and X-ray diffraction analysis of 2b, 2d, 3d and 4c allowed to assign the relative configuration of the newly formed stereogenic centers.     

Asymmetric synthesis of α,β-substituted β-aminoalkanamides and stereochemical determination

Highly enantiomerically enriched β-aminoalkanamides 12 and β-phenylaminoalkanamides 13 have been prepared by the addition reaction of α-lithiated 2-alkyl-2-oxazolines 9-Li, derived from optically active oxazolines 9, to N-cumyl nitrones 2. The relative stereochemistry of alkanamides 5 and 6 has been established by 1D-NOESY experiments carried out on the related pyrimidinones 7, whereas the absolute configuration of alkanamides 12 and 13 has been confirmed by an X-ray analysis.     

Synthesis of 3-substituted-4-hydroxyquinoline N-oxides from the Baylis-Hillman adducts of o-nitrobenzaldehydes

The reaction of the Baylis-Hillman adducts 1b-f derived from o-nitrobenzaldehydes in trifluoroacetic acid in the presence of triflic acid (0.2 equiv.) afforded 3-substituted-4-hydroxyquinoline N-oxides 2b-e and 2a in good to moderate yields. The reaction mechanism was evidenced by the experiment with 1f, the Baylis-Hillman adduct of 2-nitrobenzaldehyde N-tosylimine, as the one involving N-hydroxyisoxazoline as the key intermediate.