Internal-Edge-Substituted Coumarin-Fused [6]Helicenes: Asymmetric Synthesis, Structural Features, and Control of Self-Assembly.

π-Conjugated helicenes containing heteroatoms have attracted significant attention due to their diverse chemical and electronic structures, as well as tunable physical properties. It was rationally anticipated that the self-assembly of coumarin-fused helicenes would be controlled by the effects of a substituent on the internal edge of the helix. Here, this work reports the efficient syntheses of coumarin-fused helicenes 1 a,b (R=Ph, Me), and the enantioselective synthesis of 1 a (R=Ph) by chiral AuI -catalyzed hydroarylation. The helical structure of 1 was unambiguously determined by X-ray crystallography. Of particular note, the enantiomerically pure crystal of 1 a adopted a one-dimensional columnar structure based on π-π stacking interactions, as expected. Furthermore, a significant difference between the fluorescence quantum yields of the enantiomerically pure form and racemate of 1 a was observed.

Rational Design and Synthesis of [5]Helicene-Derived Phosphine Ligands and Their Application in Pd-Catalyzed Asymmetric Reactions.

A series of novel optically active [5]helicene-derived phosphine ligands (L1, with a 7,8-dihydro[5]helicene core structure- and L2, with a fully aromatic [5]helicene core structure) were synthesized. Despite their structural similarities, L1 and L2 exhibit particularly different characteristics in their use as chiral ligands. L1 was highly effective in the asymmetric allylation of indoles with 1,3-diphenylallyl acetate (up to 99% ee), and in the etherification of alcohols (up to 96% ee). In contrast, L2 was highly effective in the stereocontrol of helical chirality in Suzuki-Miyaura coupling (SMC) reaction (up to 99% ee). Density functional theory analysis was employed to propose a model that accounts for the origin of the enantioselectivity in these reactions.

Synthesis and Electron Paramagnetic Resonance Studies of Oligodeoxynucleotides Containing 2-N-tert-Butylaminoxyl-2'-deoxyadenosines.

Oligodeoxynucleotides (ODNs) containing 2-N-tert-butylaminoxyl-2'-deoxyadenosine (A*) residues were synthesized to allow accurate monitoring of adenine motion by EPR spectroscopy through the agency of direct linkage of the acyclic aminoxyl group to the nucleobase, and EPR studies of the ODNs in single- and double-stranded forms were performed. Upon duplex formation, peak broadening and decreases in peak height were observed in EPR spectra, and the synthesized ODNs were shown to be excellent monitors of hybridization. Comparison of peak height and the h1 /h0 signal ratio provided information on the relative mobility of A* in duplexes with different stability. A second set of ODNs each containing two A* residues at different intervals and four dA residues were also synthesized. For these ODNs, correlations were observed between the EPR spectral shapes of the duplexes and the number of dA residues between A* residues, thus demonstrating the potential of A* residues in monitoring of the structures of nucleic acids.

Site-Specific Turn-On Fluorescent Labeling of DNA-Interacting Protein Using Oligodeoxynucleotides That Modify Lysines To Produce 5,6-Dimethoxy 3-Methyleneisoindolin-1-one.

We have developed oligodeoxynucleotides (ODNs) that modify primary amines to produce 5,6-dimethoxy 3-methyleneisoindolin-1-one. Compared to the oxygen isosteric fluorophore, 4,5-dimethoxyphthalimide, this methyleneisoindolinone was more stable and exhibited an 85 nm blue-shifted fluorescent emission (λmax at 425 nm) with an intensity comparable to that of the phthalimide. Reaction of the DNA-binding domain of Escherichia coli DnaA protein with an ODN containing its binding sequence efficiently afforded a modified fluorescent protein at a specific lysine residue in the proximity of the ODN. A full-length DnaA protein was also successfully fluorescently labeled. These results demonstrate the potential utility of the ODNs developed in this study for the fluorescent labeling of DNA-interacting protein at the lysine residue of interest.

The side-chain hydroxy groups of a cyclic α,α-disubstituted α-amino acid promote oligopeptide 310 -helix packing in the crystalline state.

A single chiral cyclic α,α-disubstituted amino acid with side-chain methoxymethyl (MOM) protecting groups, (3S,4S)-1-amino-(3,4-dimethoxymethoxy)cyclopentanecarboxylic acid [(S, S)-Ac5 c(dOMOM) ], or side-chain hydroxy groups, (3S,4S)-1-amino-(3,4-dihydroxy)cyclopentanecarboxylic acid [(S, S)-Ac5 c(dOH) ], was attached to the N-terminal or C-terminal position of α-aminoisobutyric acid (Aib) tetrapeptide segments; i.e., we designed and synthesized four pentapeptides, Cbz-[(S, S)-Ac5 c(dOMOM) ]-(Aib)4 -OEt (1), Cbz-[(S, S)-Ac5 c(dOH) ]-(Aib)4 -OEt (2), Cbz-(Aib)4 -[(S, S)-Ac5 c(dOMOM) ]-OMe (3), and Cbz-(Aib)4 -[(S, S)-Ac5 c(dOH) ]-OMe (4). We then analyzed the peptides' structures in the crystalline state. The four peptides all folded into 310 -helical structures; 1 formed a left-handed (M) 310 -helix, 2 formed a mixture of right-handed (P) and (M) 310 -helices, 3 formed a mixture of (P) and (M) 310 -helices, and 4 formed a (P) 310 -helix, respectively. In packing mode, the molecules of peptides 1 and 3, which both possessed an Ac5 c(dOMOM) residue, were connected by intermolecular hydrogen bonds along the peptide backbone (NH···O type). On the other hand, the packing of peptides 2 and 4, which both contained an Ac5 c(dOH) residue, was based on intermolecular hydrogen bonds derived from both the peptide backbone and the side-chain hydroxy groups of the amino acid Ac5 c(dOH) (OH···O type). © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 757-768, 2016.

Regioselective Photocyclizations of Di(quinolinyl)arylamines and Tri(quinolinyl)amine with Emission Color Changes and Photoreaction-Induced Self-Assemblies.

Bis[2,4-di(trifluoromethyl)quinoline-7-yl]amine (1), bis[2,4-di(trifluoromethyl)quinoline-7-yl]methylamine (2), bis[2,4-di(trifluoromethyl)quinoline-7-yl]phenylamine derivatives, Q2 NPhX; X=NO2 (3 a), I (3 b), H (3 c), OMe (3 d), and NH2 (3 e), tris[2,4-di(trifluoromethyl)quinoline-7-yl]amine (4), and bis[2,4-di(pentafluoroethyl)quinoline-7-yl]-4-nitrophenylamine (5) were prepared as functional fluorophores. On irradiating the solution samples, 1 showed no noticeable alteration, whereas 2, 3 a-d, and 4 showed emission color changes from yellowish green to blue, indicating that a photoreaction took place. Analyses of the photoproduct based on absorption and emission spectra, (1) H NMR spectra, and X-ray crystallography indicated that photocyclization reactions occurred regioselectively and quantitatively to form bent-bent dipyridocarbazoles. In 3 a-d, the reaction rates depended on the solvent polarity and the substituent on the benzene ring. The photoreactions were accelerated with decreasing solvent polarity and with increasing electron-withdrawing character of the substituents. The photocyclization of triquinolineamine 4 was faster than that of 3 a in all solvents. The results of semiempirical quantum-chemical PM6 calculations suggested that the observed regioselective photocyclization could be explained by stabilization of the excited triplet transition state for the bent-bent form because of the molecular geometry with the CH-NQ hydrogen bonds. The solution of 5 in MeOH displayed photoreaction-induced self-assembly behavior to form twisted tape-like fibers of width 200 nm, as determined by TEM imaging.

Bioconjugation of Oligodeoxynucleotides Carrying 1,4-Dicarbonyl Groups via Reductive Amination with Lysine Residues.

We evaluated the efficacy of bioconjugation of oligodeoxynucleotides (ODNs) containing 1,4-dicarbonyl groups, a C4'-oxidized abasic site (OAS), and a newly designed 2'-methoxy analogue, via reductive amination with lysine residues. Dicarbonyls, aldehyde and ketone at C1- and C4-positions of deoxyribose in the ring-opened form of OAS allowed efficient reaction with amines. Kinetic studies indicated that reductive amination of OAS-containing ODNs with a proximal amine on the complementary strand proceeded 10 times faster than the corresponding reaction of an ODN containing an abasic site with C1-aldehyde. Efficient reductive amination between the DNA-binding domain of Escherichia coli DnaA protein and ODNs carrying OAS in the DnaA-binding sequence proceeded at the lysine residue in proximity to the phosphate group at the 5'-position of the OAS, in contrast to unsuccessful conjugation with abasic site ODNs, even though they have similar aldehydes. Theoretical calculation indicated that the C1-aldehyde of OAS was more accessible to the target lysine than that of the abasic site. These results demonstrate the potential utility of cross-linking strategies that use dicarbonyl-containing ODNs for the study of protein-nucleic acid interactions. Conjugation with a lysine-containing peptide that lacked specific affinity for ODN was also successful, further highlighting the advantages of 1,4-dicarbonyls.

Synthesis and Resolution of Substituted [5]Carbohelicenes.

Three types of racemic [5]helicenyl acetates (1a, 2, and 3a) were synthesized. The synthesis of 2 was achieved by regioselective oxidation using o-iodoxybenzoic acid. The enzymatic kinetic resolution of 1a-3a was studied. The conversion with the highest rate and ee was obtained using 1a as the substrate and lipase Amano PS-IM as the enzyme. The two enantiomers of 1-[5]helicenol 3b were separated using (1S)-10-camphorsulfonyl chloride as the chiral resolving agent.

Helical peptide-foldamers having a chiral five-membered ring amino acid with two azido functional groups.

A chiral five-membered ring α,α-disubstituted α-amino acid (R,R)-Ac5c(dN3) having two azido functional groups has been designed and synthesized. The cyclic amino acid (R,R)-Ac5c(dN3) could be efficiently converted into several cyclic amino acids with various two 1,2,3-triazole functional groups. (R,R)-Ac5c(dN3) homochiral peptides (up to hexapeptide) and (R,R)-Ac5c(dN3)-containing l-Leu-based peptides were prepared, and their conversion of azido functional groups into triazole groups was completed. The preferred conformation of oligomers, before and after the "click reaction", together with the azido gauche effect of amino acid residues were studied using FT-IR absorption, CD, (1)H NMR, and X-ray crystallographic analysis. The cyclic amino acid (R,R)-Ac5c(dN3) could be used as a helical conformation controlling residue and also has a versatile functionalizing site in its oligopeptides.

Synthesis of substituted azulenes via Pt(II)-catalyzed ring-expanding cycloisomerization.

Substituted azulenes, valuable structures for electronic devices and pharmaceuticals, have been synthesized by the platinum(II)-catalyzed intramolecular ring-expanding cycloisomerization of 1-en-3-yne with ortho-disubstituted benzene. This novel method provides an alternative route for the efficient synthesis of substituted azulenes. The reaction mechanism of selected catalytic transformations was explored using density functional calculations.

Synthesis of [5]helicenes with a substituent exclusively on the interior side of the helix by metal-catalyzed cycloisomerization.

[5]Helicenes with a substituent exclusively oriented toward the interior curvature of the helix are synthesized by metal-catalyzed cycloisomerization. In addition, novel azulene-fused helicenes have been found through cycloisomerization studies. These [5]helicenes shows a high enough configurationally stability to allow resolution by HPLC on a chiral stationary phase.

Difluoro-C4'-oxidized abasic site for efficient amine modification in biological systems.

An oligodeoxynucleotide (ODN) containing a 2',2'-difluorinated analogue of a C4'-oxidized abasic site (C4'-OAS) was designed for the amine modification of biomolecules that interact with nucleic acids. In contrast to the parent C4'-OAS, which yielded amine-modified products accompanied by DNA strand scission, the ODN containing the difluoro C4'-OAS efficiently yielded products carrying ODNs. The amine modification proceeded without additional reagents being required and might be applicable to reactions in biological systems.

Design and optimization of novel (2S,4S,5S)-5-amino-6-(2,2-dimethyl-5-oxo-4-phenylpiperazin-1-yl)-4-hydroxy-2-isopropylhexanamides as renin inhibitors.

Introduction of the 2,2-dimethyl-4-phenylpiperazin-5-one scaffold into the P(3)-P(1) portion of the (2S,4S,5S)-5-amino-6-dialkylamino-4-hydroxy-2-isopropylhexanamide backbone dramatically increased the renin inhibitory activity without using the interaction to the S(3)(sp) pocket. Compound 31 exhibited >10,000-fold selectivity over other human proteases, and 18.5% oral bioavailability in monkey.

Synthesis and characterization of 1,8-naphthalimide with [6]helicene skeleton.

A 1,8-naphthalimide with [6]helicene derivative scaffold has been designed and synthesized. The (P)- and (M)-enantiomers of the [6]helicene derivative were resolved by HPLC on a chiral column. The single crystal of the [6]helicene derivative exhibits an intermolecular interactions of the 1,8-naphthalimide units.

One-handed helical screw direction of homopeptide foldamer exclusively induced by cyclic α-amino acid side-chain chiral centers.

Chiral cyclic α,α-disubstituted amino acids, (3S,4S)- and (3R,4R)-1-amino-3,4-(dialkoxy)cyclopentanecarboxylic acids ((S,S)- and (R,R)-Ac(5)c(dOR); R: methyl, methoxymethyl), were synthesized from dimethyl L-(+)- or D-(-)-tartrate, and their homochiral homoligomers were prepared by solution-phase methods. The preferred secondary structure of the (S,S)-Ac(5)c(dOMe) hexapeptide was a left-handed (M) 3(10) helix, whereas those of the (S,S)-Ac(5)c(dOMe) octa- and decapeptides were left-handed (M) α helices, both in solution and in the crystal state. The octa- and decapeptides can be well dissolved in pure water and are more α helical in water than in 2,2,2-trifluoroethanol solution. The left-handed (M) helices of the (S,S)-Ac(5)c(dOMe) homochiral homopeptides were exclusively controlled by the side-chain chiral centers, because the cyclic amino acid (S,S)-Ac(5)c(dOMe) does not have an α-carbon chiral center but has side-chain γ-carbon chiral centers.

Dialkyl bisphosphonate platinum(II) complex as a potential drug for metastatic bone tumor.

Bisphosphonates have high affinity for hydroxyapatite (HA), which is abundantly present in bone. Also, platinum complexes are known that have a wide spectrum of antitumor activities. The conjugate of bisphosphonate and a platinum complex might have HA affinity and antitumor activity, and become a drug for metastatic bone tumor. In this study, the authors synthesized platinum complexes that had dialkyl bisphosphonic acid as a ligand, and evaluated the possibility of the synthesized complexes as a drug for metastatic bone tumor. The synthesized dialkyl bisphosphonate platinum(II) complex was characterized, and its stability in an aqueous solution was also confirmed. The synthesized platinum complex showed higher HA affinity than other platinum complexes such as cisplatin and carboplatin in an experiment of adsorption to HA. In vitro, the platinum complex showed tumor growth inhibitory effect stronger than or equal to cisplatin, which is the most commonly used antitumor agent. Moreover, the platinum complex showed a bone absorption inhibitory effect on the osteoclast. These results suggest potential of dialkyl bisphosphonate platinum(II) complexes as a drug for metastatic bone tumor.

Conformational studies on peptides containing α,α-disubstituted α-amino acids: chiral cyclic α,α-disubstituted α-amino acid as an α-helical inducer.

Four types of α,α-disubstituted amino acids {i.e., α-aminoisobutyric acid (Aib), 1-aminocyclopentanecarboxylic acid (Ac(5)c), (3S,4S)-1-amino-(3,4-dimethoxy)cyclopentanecarboxylic acid [(S,S)-Ac(5)c(dOM)] and its enantiomer (R,R)-Ac(5)c(dOM)} were introduced into l-leucine-based hexapeptides and nonapeptides. The dominant conformations of eight peptides: Cbz-(L-Leu-L-Leu-dAA)(2)-OMe [dAA = 1: Aib; 2: Ac(5)c; 3: (S,S)-Ac(5)c(dOM); 4: (R,R)-Ac(5)c(dOM)] and Boc-(L-Leu-L-Leu-dAA)(3)-OMe [dAA = 5: Aib; 6: Ac(5)c; 7: (S,S)-Ac(5)c(dOM); 8: (R,R)-Ac(5)c(dOM)], were investigated by IR, CD spectra and X-ray crystallographic analysis. The CD spectra revealed that Aib hexapeptide 1 and Ac(5)c hexapeptide 2 formed right-handed (P) 3(10)-helices, while Ac(5)c(dOM) hexapeptides 3 and 4 formed a mixture of (P) 3(10)- and α-helices. The Aib nonapeptide 5 formed a (P) 3(10)-helix, the Ac(5)c nonapeptide 6 formed a mixture of (P) 3(10)- and α-helices, and the Ac(5)c(dOM) nonapeptides 7 and 8 formed (P) α-helices. X-Ray crystallographic analysis revealed that the Aib hexapeptide 1 formed a (P) 3(10)-helix, while (S,S)-Ac(5)c(dOM) hexapeptide 3 formed a (P) α-helix. In addition, the Ac(5)c nonapeptide 6 and (R,R)-Ac(5)c(dOM) nonapeptide 8 formed (P) α-helices. The Aib and achiral Ac(5)c residues have the propensity to form 3(10)-helices in short peptides, whereas the chiral Ac(5)c(dOM) residues have a penchant for forming α-helices.

Conformations of peptides containing a chiral cyclic α, α-disubstituted α-amino acid within the sequence of Aib residues.

A single chiral cyclic α,α-disubstituted amino acid, (3S,4S)-1-amino-(3,4-dimethoxy)cyclopentanecarboxylic acid [(S,S)-Ac(5)c(dOM)], was placed at the N-terminal or C-terminal positions of achiral α-aminoisobutyric acid (Aib) peptide segments. The IR and (1)H NMR spectra indicated that the dominant conformations of two peptides Cbz-[(S,S)-Ac(5)c(dOM)]-(Aib)(4)-OEt (1) and Cbz-(Aib)(4)-[(S,S)-Ac(5)c(dOM)]-OMe (2) in solution were helical structures. X-ray crystallographic analysis of 1 and 2 revealed that a left-handed (M) 3(10)-helical structure was present in 1 and that a right-handed (P) 3(10)-helical structure was present in 2 in their crystalline states.

Stabilized alpha-helix-catalyzed enantioselective epoxidation of alpha,beta-unsaturated ketones.

Chiral cyclic alpha-amino acid containing oligopeptide catalyzed highly enantioselective epoxidation of alpha,beta-unsaturated ketones and the alpha-helical secondary structure of the peptide catalyst were revealed by X-ray crystallographic analysis.

Asymmetric Rh-catalyzed intermolecular hydroacylation of 1,5-hexadiene with salicylaldehyde.

Asymmetric intermolecular hydroacylation between salicylaldehyde (1) and 1,5-hexadiene (2) using a combination of [RhCl(C(8)H(14))(2)](2) (0.10 eq), (S)-BINAP (0.10 eq), and ZnBr(2) (0.20 eq) afforded an enantiomerically enriched hydroacylated product iso-3 of 84% ee, along with an achiral product normal-3.