Preparation of (S,S)‐Fmoc‐β2hIle‐OH, (S)‐Fmoc‐β2hMet‐OH,and (S)‐Fmoc‐β2hTyr(tBu)‐OH for Solid‐Phase Syntheses of β2‐ and β2/β3‐Peptides

The preparation of three new N‐Fmoc‐protected (Fmoc=[(9H‐fluoren‐9‐yl)methoxy]carbonyl) β²‐homoamino acids with proteinogenic side chains (from Ile, Tyr, and Met) is described, the key step being a diastereoselective amidomethylation of the corresponding Ti‐enolates of 3‐acyl‐4‐isopropyl‐5,5‐diphenyloxazolidin‐2‐ones with CbzNHCH₂OMe/TiCl₄ (Cbz=(benzyloxy)carbonyl) in yields of 60–70% and with diastereoselectivities of >90%. Removal of the chiral auxiliary with LiOH or NaOH gives the N‐Cbz‐protected β‐amino acids, which were subjected to an N‐Cbz/N‐Fmoc (Fmoc=[(9H‐fluoren‐9‐yl)methoxy]carbonyl) protective‐group exchange. The method is suitable for large‐scale preparation of Fmoc‐β²hXaa‐OH for solid‐phase syntheses of β‐peptides. The Fmoc‐amino acids and all compounds leading to them have been fully characterized by melting points, optical rotations, IR, ¹H‐ and ¹³C‐NMR, and mass spectra, as well as by elemental analyses.     

Oligonucleotide Analogues with a ‘Nucleobase‐Including Backbone’. Part 10

The dinucleoside analogues 24, 25, 28 – 30 , and 33 associate in CDCl₃ solution. Association constants, as determined from the concentration‐dependent chemical shift for H? N(3) of the uridine moiety and from thermodynamic parameters, range from 265 M ^?1 ( 33 ) to 3220 M ^?1 ( 30 ). The association of 31 in CDCl₃ is too strong to be determined (concentration independent δ(H? N(3)) of ca. 12.8 ppm) and the fully deprotected dimer 32 proved insufficiently soluble in CDCl₃. This observation strongly evidences that structural differentiation of oligonucleotides and their analogues into backbone and nucleobases is not required for pairing. The dinucleotide analogues were prepared by O‐alkylation of C(8)‐unsubstituted or of C(8)‐oxymethylated, partially protected adenosines by the C(6)‐mesyloxy‐ or C(6)‐halomethylated uridines 20 – 22 , followed by partial or total deprotection.     

Synthesis,experimental and in silico studies of N‐fluorenylmethoxycarbonyl‐O‐tert‐butyl‐N‐methyltyrosine,coupled with CSD data: a survey of interactions in the crystal structures of Fmoc–amino acids

Recently, fluorenylmethoxycarbonyl (Fmoc) amino acids (e.g. Fmoc–tyrosine or Fmoc–phenylalanine) have attracted growing interest in biomedical research and industry, with special emphasis directed towards the design and development of novel effective hydrogelators, biomaterials or therapeutics. With this in mind, a systematic knowledge of the structural and supramolecular features in recognition of those properties is essential. This work is the first comprehensive summary of noncovalent interactions combined with a library of supramolecular synthon patterns in all crystal structures of amino acids with the Fmoc moiety reported so far. Moreover, a new Fmoc‐protected amino acid, namely, 2‐{[(9H‐fluoren‐9‐ylmethoxy)carbonyl](methyl)amino}‐3‐{4‐[(2‐hydroxypropan‐2‐yl)oxy]phenyl}propanoic acid or N‐fluorenylmethoxycarbonyl‐O‐tert‐butyl‐N‐methyltyrosine, Fmoc‐N‐Me‐Tyr(t‐Bu)‐OH, C₂₉H₃₁NO₅, was successfully synthesized and the structure of its unsolvated form was determined by single‐crystal X‐ray diffraction. The structural, conformational and energy landscape was investigated in detail by combined experimental and in silico approaches, and further compared to N‐Fmoc‐phenylalanine [Draper et al. (2015). CrystEngComm, 42 , 8047–8057]. Geometries were optimized by the density functional theory (DFT) method either in vacuo or in solutio. The polarizable conductor calculation model was exploited for the evaluation of the hydration effect. Hirshfeld surface analysis revealed that H…H, C…H/H…C and O…H/H…O interactions constitute the major contributions to the total Hirshfeld surface area in all the investigated systems. The molecular electrostatic potentials mapped over the surfaces identified the electrostatic complementarities in the crystal packing. The prediction of weak hydrogen‐bonded patterns via Full Interaction Maps was computed. Supramolecular motifs formed via C—H…O, C—H…π, (fluorenyl)C—H…Cl(I), C—Br…π(fluorenyl) and C—I…π(fluorenyl) interactions are observed. Basic synthons, in combination with the Long‐Range Synthon Aufbau Modules, further supported by energy‐framework calculations, are discussed. Furthermore, the relevance of Fmoc‐based supramolecular hydrogen‐bonding patterns in biocomplexes are emphasized, for the first time.     

Biocomplementary interaction behavior in DNA‐like and RNA‐like polymers

A series of nucleobased polymers and copolymers were synthesized through atom transfer radical polymerization (ATRP). Biocomplementary DNA‐ and RNA‐like supramolecular complexes are formed in dilute DMSO solution through nucleobase recognition. ¹H NMR titration studies of these complexes in CDCl₃ indicated that thymine‐adenine (T‐A) and uracil‐adenine (U‐A) complexes form rapidly on the NMR time scale with high association constants (up to 534 and 671 M^–1, respectively) and result in significant T_g increase. WAXD and differential scanning calorimetry analyzes in the bulk state indicate the presence of highly physical cross‐linked structures and provide further details into the nature of the self‐assembly of these systems. Furthermore, this study is of discussion on the difference in the hydrogen bond strength between T‐A and U‐A base pairs within polymer systems, indicating that the strength of hydrogen bonds in RNA U‐A pairs is stronger than that in DNA T‐A base pairs. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 6388–6395, 2009     

Characterization of Nα-Fmoc-protected ureidopeptides by electrospray ionization tandem mass spectrometry (ESI-MS/MS): differentiation of positional isomers

Four pairs of positional isomers of ureidopeptides, FmocNH‐CH(R₁)‐φ(NH‐CO‐NH)‐CH(R₂)‐OY and FmocNH‐CH(R₂)‐φ(NH‐CO‐NH)‐CH(R₁)‐OY (Fmoc = [(9‐fluorenyl methyl)oxy]carbonyl; R₁ = H, alkyl; R₂ = alkyl, H and Y = CH₃/H), have been characterized and differentiated by both positive and negative ion electrospray ionization (ESI) ion‐trap tandem mass spectrometry (MS/MS). The major fragmentation noticed in MS/MS of all these compounds is due to ? N? CH(R)? N? bond cleavage to form the characteristic N‐ and C‐terminus fragment ions. The protonated ureidopeptide acids derived from glycine at the N‐terminus form protonated (9H‐fluoren‐9‐yl)methyl carbamate ion at m/z 240 which is absent for the corresponding esters. Another interesting fragmentation noticed in ureidopeptides derived from glycine at the N‐terminus is an unusual loss of 61 units from an intermediate fragment ion FmocNH = CH₂⁺ (m/z 252). A mechanism involving an ion‐neutral complex and a direct loss of NH₃ and CO₂ is proposed for this process. Whereas ureidopeptides derived from alanine, leucine and phenylalanine at the N‐terminus eliminate CO₂ followed by corresponding imine to form (9H‐fluoren‐9‐yl)methyl cation (C₁₄H₁₁⁺) from FmocNH = CHR⁺. In addition, characteristic immonium ions are also observed. The deprotonated ureidopeptide acids dissociate differently from the protonated ureidopeptides. The [M ? H]^? ions of ureidopeptide acids undergo a McLafferty‐type rearrangement followed by the loss of CO₂ to form an abundant [M ? H ? Fmoc + H]^? which is absent for protonated ureidopeptides. Thus, the present study provides information on mass spectral characterization of ureidopeptides and distinguishes the positional isomers. Copyright © 2010 John Wiley & Sons, Ltd.     

Oligonucleotide Analogues with Integrated Bases and Backbone (ONIB). Part 31

The self‐complementary guanosine‐ and cytidine‐derived aminomethylene‐linked C*[n ]G dinucleoside 9 was synthesized by reductive amination of aldehyde 3 with an iminophosphorane derived from azide 7 . Deacylation of 9 gave the isopropylidene‐protected dinucleoside 10 . The sequence‐isomeric G*[n ]C dinucleoside 11 was similarly prepared from aldehyde 8 and azide 5 , and deacylated to 12 . The association of 10 and 12 in CHCl₃ or in CHCl₃/DMSO mixtures, and the structure of the associates were studied by ¹H‐NMR, ESI‐MS, CD, and vapor pressure osmometry (VPO). Broad ¹H‐NMR signals of dinucleosides 10 and 12 evidence an equilibrium between duplexes and quadruplexes (Hoogsteen base pairing between the Watson? Crick base‐paired duplexes). The quadruplex dominates for the G*[n ]C dinucleoside 12 between ?50° and room temperature. The sequence‐isomeric C*[n ]G 10 forms mostly only a cyclic duplex in CDCl₃ and in CDCl₃/(D₆)DMSO 9 : 1.     

Synthesis of some pyrazole‐3‐carboxylic acid‐hydrazide and pyrazolopyridazine compounds

Furan‐2,3‐diones 1a‐c react with various hydrazines 2a‐c under different conditions to yield the pyrazole‐3‐carboxylic acid‐hydrazide 3a‐d . Cyclocondensation reactions of 1a or 7 with phenylhydrazine lead to derivatives of pyrazolo[3,4‐d]pyridazinones 6 and 8 , respectively. The structures of all products were confirmed by elemental analysis, IR, ¹H‐ and ¹³C‐NMR spectroscopic measurements.     

Oligonucleotide Analogues with Integrated Bases and Backbone. Part 22

The tritylated and silylated self‐complementary A*[s]U*[s]A*[s]U* and U*[s]A*[s]U*[s]A* tetramers 18 and 24 , linked by thiomethylene groups (abbreviated as [s]) between a nucleobase and C(5′) of the neighbouring nucleoside unit were prepared by a linear synthesis based on S‐alkylation of 5′‐thionucleosides by 6‐(chloromethyl)uridines, 7 or 10 , or 8‐(chloromethyl)adenosines, 12 or 15 . The tetramers 18 and 24 were detritylated to the monoalcohols 19 and 25 , and these were desilylated to the diols 20 and 26 , respectively. The association of the tetramers 18 – 21 and 24 – 26 in CDCl₃ or in CDCl₃/(D₆)DMSO 95 : 5 was investigated by the concentration dependence of the chemical shifts for H? N(3) or H₂N? C(6). The formation of cyclic duplexes connected by four base pairs is favoured by the presence of one and especially of two OH groups. The diol 20 with the AUAU sequence prefers reverse‐Hoogsteen, and diol 26 with the UAUA sequence Watson–Crick base pairing. The structure of the cyclic duplex of 26 in CDCl₃ at 2° was derived by a combination of AMBER* modeling and simulated annealing with NMR‐derived distance and torsion‐angle restraints resulting in a Watson–Crick base‐paired right‐handed antiparallel helix showing large roll angles, especially between the centre base pairs, leading to a bent helix axis.     

Synthesis of N′-substituted Ddz-protected hydrazines and their application in solid phase synthesis of aza-peptides

Hydrazine derivatives are of considerable scientific and industrial value. Substituted hydrazines are precursors for many compounds of great interest and importance, among them aza-peptides. (Aza-peptides are peptide analogues in which one or more of the α-carbons, bearing the side chain residues, has been replaced by a nitrogen atom.) Aza-amino acid residues conserve the pharmacophores necessary for biological activity while inducing conformational changes and increased resistance to proteolytic degradation. These properties make aza-peptides attractive tools for structure-activity relationship studies and drug design. We describe the synthesis of N′-substituted 2-(3,5-dimethoxyphenyl)propan-2-yloxycarbonyl (Ddz) protected hydrazines. A general approach for solid phase synthesis of aza-peptides has been developed based on the in-situ activation of the N-Ddz,N′-substituted hydrazines with phosgene, followed by introduction to the N-terminus of a resin-bound peptide. The Ddz-aza-amino building units include aliphatic, aromatic and functionalized side chains, protected for synthesis by the Fmoc strategy. Solid phase aza-peptide synthesis is demonstrated including selective mild deprotection of Ddz with Mg(ClO₄)₂ and coupling of the next amino acid with triphosgene. Ddz deprotection is orthogonal with the Fmoc and Boc protecting groups, making the solid phase Ddz-aza-peptide synthesis compatible with both the Fmoc and the Boc strategies. The Ddz-protected hydrazines have wide applications in the synthesis of substituted hydrazines and in the synthesis of aza containing peptidomimetics.     

Mononuclear Tetraamineplatinum(II) Complexes: Synthesis,Anticancer Activity,DNA Binding,and Cellular Uptake

The synthesis of three bis[(tert‐butoxy)carbonyl]‐protected (tetramine)dichloroplatinum complexes 2a – c of formula cis‐[PtCl₂(LL)] and of their cationic deprotected analogs 3a – c and their evaluation with respect to in vitro cytotoxicity, intramolecular stability, DNA binding, and cellular uptake is reported. The synthesis comprises the complexation of K₂[PtCl₄] with di‐N‐protected tetramines 1a – c to give 2a – c and subsequent acidolysis, yielding 3a – c . The cytotoxicity of the complexes is in direct relation to the length of the polyamine. Complexes 3a – c display a significant higher affinity for CT DNA as well as for cellular DNA in A2780 cells than cisplatin.     

Oligonucleotide Analogues with Integrated Bases and Backbones. Part 24

Inspection of Maruzen models and force‐field calculations suggest that oligonucleotide analogues integrating backbone and bases (ONIBs) with an aminomethylene linker form similar cyclic duplexes as the analogous oxymethylene linked dinucleosides. The self‐complementary adenosine‐ and uridine‐derived aminomethylene‐linked A*[n ]U dinucleosides 15 – 17 were prepared by an aza‐Wittig reaction of the aldehyde 10 with an iminophosphorane derived from azide 6 . The sequence‐isomeric U*[n ]A dinucleosides 18 – 20 were similarly prepared from aldehyde 3 and azide 12 . The N‐ethylamine 5 , the acetamides 7 and 14 , and the amine 13 were prepared as references for the conformational analysis of the dinucleosides. In contradistinction to the results of calculations, the N‐ethylamine 5 exists as intramolecularly H‐bonded hydroxyimino tautomer. The association in CDCl₃ of these dinucleosides was studied by ¹H‐NMR and CD spectroscopy. The A*[n ]U dinucleosides 16 and 17 associate more strongly than the sequence isomers 19 and 20 ; the cyclic duplexes of 16 form preferentially Watson–Crick‐type base pairs, while 17, 19 , and 20 show both Watson–Crick‐ and Hoogsteen‐type base pairing. The cyclic duplexes of the aminomethylene‐linked dinucleosides prefer a gg‐orientation of the linker. No evidence was found for an intramolecular H‐bond of the aminomethylene group. The CD spectra of 16 and 17 show a strong, those of 19 a weak, and those of 20 almost no temperature dependence.     

Synthesis and characterization of novel (9H‐fluoren‐9‐ylamino) carbonylaminomethylphosphonic acid

The new α‐aminophosphonic acids are synthesized, reacting (9H‐fluoren‐9‐yl)urea with formaldehyde and phosphorus trichloride. (9H‐Fluoren‐9‐yl)urea was prepared from spiro(fluoren‐9,4′‐imidazolidine)‐2′,5′‐dione by alkaline hydrolysis with Ba(OH)₂. The structure of the title compounds was proved by means of IR, ¹H, ¹³C, and ³¹P NMR spectroscopy. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:719–722, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20500     

Oligonucleotide Analogues with Integrated Bases and Backbone. Part 17

The formation of cyclic duplexes (pairing) of known oxymethylene‐linked self‐complementary U*[o]A⁽*⁾ dinucleosides contrasts with the absence of pairing of the ethylene‐linked U*[c_a]A⁽*⁾ analogues. The origin of this difference, and the expected association of U*[x]A⁽*⁾ and A*[x]U⁽*⁾ dinucleosides with x=CH₂, O, or S was analysed. According to this analysis, pairing occurs via constitutionally isomeric Watson–Crick, reverse Watson–Crick, Hoogsteen, or reverse Hoogsteen H‐bonded linear duplexes. Each one of them may give rise to three diastereoisomeric cyclic duplexes, and each one of them can adopt three main conformations. The relative stability of all conformers with x=CH₂, O, or S were analysed. U*[x]A⁽*⁾ dinucleosides with x=CH₂ do not form stable cyclic duplexes, dinucleosides with x=O may form cyclic duplexes with a gg‐conformation about the C(4′)? C(5′) bond, and dinucleosides with x=S may form cyclic duplexes with a gt‐conformation about this bond. The temperature dependence of the chemical shift of H? N(3) of the self‐complementary, oxymethylene‐linked U*[o]A⁽*⁾ dinucleosides 1 – 6 in CDCl₃ in the concentration range of 0.4–50 mM evidences equilibria between the monoplex, mainly linear duplexes, and higher associates for 3 , between the monoplex and cyclic duplexes for 6 , and between the monoplex, linear, and cyclic duplexes as well as higher associates for 1, 2, 4 , and 5 . The self‐complementary, thiomethylene‐linked U*[s]A⁽*⁾ dinucleosides 27 – 32 and the sequence isomeric A*[s]U⁽*⁾ analogues 33 – 38 were prepared by S‐alkylation of the 6‐(mesyloxymethyl)uridine 12 and the 8‐(bromomethyl)adenosine 22 . The required thiolates were prepared in situ from the C(5′)‐acetylthio derivatives 9, 15, 19 , and 25 . The association in CHCl₃ of the thiomethylene‐linked dinucleoside analogues was studied by ¹H‐NMR and CD spectroscopy, and by vapour‐pressure osmometric determination of the apparent molecular mass. The U*[s]A⁽*⁾ alcohols 28, 30 , and 31 form cyclic duplexes connected by Watson–Crick H‐bonds, while the fully protected dimers 27 and 29 form mainly linear duplexes and higher associates. The diol 32 forms mainly cyclic duplexes in solution and corrugated ribbons in the solid state. The nucleobases of crystalline 32 form reverse Hoogsteen H‐bonds, and the resulting ribbons are cross‐linked by H‐bonds between HOCH₂? C(8/I) and N(3/I). Among the A*[s]U⁽*⁾ dimers, only the C(8/I)‐hydroxymethylated 37 forms (mainly) a cyclic duplex, characterized by reverse Hoogsteen base pairing. The dimers 34 – 36 form mainly linear duplexes and higher associates. Dimers 34 and particularly 38 gelate CHCl₃. Temperature‐dependent CD spectra of 28, 30, 31 , and 37 evidence π‐stacking in the cyclic duplexes. Base stacking in the particularly strongly associating diol 32 in CHCl₃ solution is evidenced by a melting temperature of ca. 2°.     

Solid‐Phase Synthesis of a β‐Dodecapeptide with Seven Functionalized Side Chains and CD‐Spectroscopic Evidence for a Dramatic Structural Switch When Going from Water to Methanol Solution

An all‐β³‐dodecapeptide with a protected N‐terminal thiol‐anchoring group and with seven side chains has been synthesized in multi‐mg amounts by the manual solid‐phase technique, applying Fmoc methodology and the Wang resin. The sequence is β‐HLys‐β‐HPhe‐β‐HTyr‐β‐HLeu‐β‐HLys‐β‐HSer‐β‐HLys‐β‐HPhe‐β‐HSer‐β‐HVal‐β‐HLys‐β‐HAla‐OH (from N‐ to C‐terminus; see 1 ). The functional groups in the side chains of the building blocks were Boc (β‐HLys) or t‐Bu ether (β‐HSer, β‐HTyr) protected to allow for simultaneous deprotection and detachment from the resin with trifluoroacetic acid. All coupling steps were achieved with HBTU (=O‐(1H‐benzotriazol‐1‐yl)‐1,1,3,3‐tetramethyl uronium hexafluorophosphate)/HOBt (=1‐hydroxy‐1H‐benzotriazole) in DMF. For Fmoc (=(9H‐fluoren‐9‐yl)methoxycarbonyl) deprotection, a protocol was developed to surmount the previously reported problems arising in solid‐phase synthesis of β‐peptides when the chain length exceeds seven or eight amino‐acid moieties: for up to seven amino acids, a 20% solution of piperidine in DMF was used for removal of Fmoc; for the subsequent five amino acids, DBU and piperidine were employed for complete deprotection. The crude product was purified by preparative reversed‐phase HPLC, and the yield of pure β‐dodecapeptide derivative ( 1 ) was 23%. As the compound is well‐soluble in H₂O, it was characterized by ¹H‐NMR (in MeOH and H₂O), ¹³C‐NMR (in MeOH), and CD spectroscopy (in MeOH and in H₂O at pH values ranging from 3.5 to 11), and its molecular weight and composition were confirmed by high‐resolution mass spectrometry (Figs. 1 – 4). In MeOH solution, the β‐dodecapeptide exhibits the expected CD pattern typical of an (M)‐3₁₄‐helical secondary structure. In H₂O, however, the characteristic trough near 215 nm is missing in the CD spectrum, only a strong positive Cotton effect at 202 nm was observed, indicating the presence of β‐peptidic secondary structures, containing ten‐membered H‐bonded rings, such as the 12/10 helix (Fig. 4, right) or the hairpin. Only a detailed NMR solution‐structure analysis will provide the clues necessary for understanding the effects leading to the observed dramatic structural change of the highly functionalized β‐dodecapeptide described.     

Synthesis of 9‐Halogenated 9‐Deazaguanine N7‐(2′‐Deoxyribonucleosides)

The syntheses of N⁷‐glycosylated 9‐deazaguanine 1a as well as of its 9‐bromo and 9‐iodo derivatives 1b , c are described. The regioselective 9‐halogenation with N‐bromosuccinimide (NBS) and N‐iodosuccinimide (NIS) was accomplished at the protected nucleobase 4a (2‐{[(dimethylamino)methylidene]amino}‐3,5‐dihydro‐3‐[(pivaloyloxy)methyl]‐4H‐pyrrolo[3,2‐d]pyrimidin‐4‐one). Nucleobase‐anion glycosylation of 4a – c with 2‐deoxy‐3,5‐di‐O‐(p‐toluoyl)‐α‐D ‐erythro‐pentofuranosyl chloride ( 5 ) furnished the fully protected intermediates 6a – c (Scheme 2). They were deprotected with 0.01M NaOMe yielding the sugar‐deprotected derivatives 8a – c (Scheme 3). At higher concentrations (0.1M NaOMe), also the pivaloyloxymethyl group was removed to give 7a – c , while conc. aq. NH₃ solution furnished the nucleosides 1a – c . In D₂O, the sugar conformation was always biased towards S (67–61%).     

Design and Synthesis of Nucleoproline Amino Acids for the Straightforward Preparation of Chiral and Conformationally Constrained Nucleopeptides

A straightforward synthesis of orthogonally protected nucleoproline (Nup) amino acids and their coupling to oligomers are described. A key step is the attachment of alkynylated nucleobases to Fmoc‐protected 4‐azidoproline (Fmoc‐Azp‐OH) by a Cu‐catalyzed 1,3‐dipolar cycloaddition (‘click reaction’). The developed protocol allows preparation of the nucleoprolines in scales of >30 g. Solid‐phase peptide synthesis proved to be straightforward with these Nup amino acids. The resulting oligonucleoproline peptides adopt defined helices, are very well H₂O soluble, and show comparable cell‐penetrating properties as recently reported α‐nucleoalanine peptides.     

Helix‐Forming Oligoureas: Temperature‐Dependent NMR,Structure Determination,and Circular Dichroism of a Nonamer with Functionalized Side Chains

To further investigate the degree of structural homology between γ‐peptides A and N,N′‐linked oligoureas B , we prepared oligourea nonamer 2 containing Ala, Val, Leu, Phe, Tyr and Lys side chains. Oligomer 2 was synthesized on solid support from activated monomers, i.e., from enantiomerically pure succinimidyl {2‐{[(9H‐fluoren‐9‐ylmethoxy)carbonyl]amino}ethyl}carbamates 3a – f that are further substituted at C(2) of the ethyl moiety. These precursors were conveniently prepared from N‐Fmoc‐protected β³‐amino acids with corresponding side chains. Detailed NMR studies (DQF‐COSY, TOCSY, and ROESY) in (D₅)pyridine revealed that 2 adopts a regular (P)‐2.5 helical secondary structure very similar to that previously determined for oligourea heptamer 1 and closely related to the (P)‐2.6₁₄ helix of γ‐peptides. Temperature‐dependent NMR further demonstrated the conformational homogeneity and remarkable stability of the structure of 2 in pyridine. The CD spectrum of 2 (0.2 mM ) was recorded in MeOH with the aim to gain more information about the conformation of oligoureas. In contrast to 2.6‐helical γ‐peptides, which display only a weak or no Cotton effect, oligourea 2 exhibits an intense positive Cotton effect at ca. 203 nm ([Θ]=+373000 deg cm² dmol⁻¹) that decreases only slowly upon increasing the temperature.     

4‐Vinyl­benzyl analogs of adenine and uracil: reactive monomers for nucleobase polymeric resins

The crystal structures of 9‐(4‐vinyl­benzyl)­adenine, C₁₄H₁₃N₅, and 1‐(4‐vinyl­benzyl)­uracil, C₁₃H₁₂N₂O₂, are composed of zigzag ribbon‐like structures that are stabilized by conventional (N—H?N‐type) hydrogen bonds for the former and conventional (N—H?O‐type) and non‐conventional (C—H?O‐type) hydrogen bonds for the latter; the hydrogen‐bonding patterns are represented by graph‐sets R(9) and R(8), respectively. The adenine and uracil moieties in these alkyl­ated derivatives are planar and are inclined at angles of 84.44 (4) and 79.07 (7)°, respectively, with respect to the phenyl rings.     

N‐Trifluoromethyl Hydrazines,Indoles and Their Derivatives

Reported herein is the first efficient strategy to synthesize a broad range of unsymmetrical N‐CF₃ hydrazines, which served as platform to unlock numerous currently inaccessible derivatives, such as tri‐ and tetra‐substituted N‐CF₃ hydrazines, hydrazones, sulfonyl hydrazines, and valuable N‐CF₃ indoles. These compounds proved to be remarkably robust, being compatible with acids, bases, and a wide range of synthetic manipulations. The feasibility of RN(CF₃)‐NH₂ to function as a directing group in C?H functionalization is also showcased.     

Ligand‐Enabled β‐C–H Arylation of α‐Amino Acids Without Installing Exogenous Directing Groups

Herein we report acid‐directed β‐C(sp³)‐H arylation of α‐amino acids enabled by pyridine‐type ligands. This reaction does not require the installation of an exogenous directing group, is scalable, and enables the preparation of Fmoc‐protected unnatural amino acids in three steps. The pyridine‐type ligands are crucial for the development of this new C(sp³)‐H arylation.