On the prebiotic synthesis of D-sugars catalyzed by L-peptides: assessments from first-principles calculations

What accounts for a particular chiral selection in the case of a few sugars of prebiotic relevance, thereby mirroring the asymmetry observed in nature? By using first-principles calculations, the generation of pentoses from glycolaldehyde (the initial product of the autocatalytic formose reaction), which has been detected in outer space), has been modeled by using L-Val-L-Val as a primeval catalyst. Our theoretical study provides insight into the mechanism of this reaction and satisfactorily explains a few key molecular events. Our rationale agrees with the reported experimental data and shows that the D-configuration is only favored for ribose. L-pentoses are usually favored in the presence of L-configured dipeptides, as observed experimentally, although no chiral selection could be observed in the case of xylose. These results confirm that a prebiotic sugar soup could be fine-tuned in the presence of shorter peptides as catalysts and that D-ribose would have also resulted in an advantageous imbalance for further amplification and chemical evolution.     

Properties and Reactions of Substituted 1,2‐Thiazetidine 1,1‐Dioxides: Chiral Mono‐ and Bicyclic 1,2‐Thiazetidine 1,1‐Dioxides from α‐Amino Acids

New chiral mono‐ and bicyclic β‐sultams, valuable building blocks for drug synthesis, have been prepared from L ‐Ala, L ‐Val, L ‐Leu, L ‐Ile, L ‐Phe, L ‐Cys, L ‐Ser, L ‐Thr, and D ‐penicillamine by transformation of the COOH group into a methylsulfonyl chloride function, followed by cyclization under basic conditions. Selected properties, derivatives, and reactions of the β‐sultams are described.     

The 5‐Methylisocytosine β‐D‐Ribopyranosyl (4′ → 2′)‐Oligonucleotide

In the context of Eschenmoser's work on pyranosyl‐RNA (‘p‐RNA’), we investigated the synthesis and base‐pairing properties of the 5‐methylisocytidine derivative. The previously determined clear‐cut restrictions of base‐pairing modes of p‐RNA had led to the expectation that a 5‐methylisocytosine β‐D ‐ribopyranosyl (= D ‐pr(^MeisoC)) based (4′ → 2′)‐oligonucleotide would pair inter alia with D ‐pr(isoG) and L ‐pr(G) based oligonucleotides (D ‐pr and L ‐pr = pyranose form of D ‐ and L ‐ribose, resp.). Remarkably, we could not observe pairing with the D ‐pr(isoG) oligonucleotide but only with the L ‐pr(G) oligonucleotide. Our interpretation concludes that this – at first hand surprising – observation is caused by a change in the nucleosidic torsion angle specific for isoC.     

A Dual‐Functional Metallogel of Amphiphilic Copper(II) Quinolinol: Redox Responsiveness and Enantioselectivity

A dual‐functional metallogel, which was based on the copper(II) complex of quinolinol‐substituted L ‐glutamide, showed both redox‐responsive and enantioselective properties; moreover, the metallogels collapsed into a sol after reduction and could be revived upon subsequent oxidation. The supramolecular chirality and morphology also reversible changed with the gel–sol transition. Furthermore, the metallogels showed new enantioselective recognition towards chiral aromatic amino acids. A new emission band in the blue‐light region at around 393 nm appeared when the metallogels encountered L ‐aromatic amino acids, whereas no new emission band was observed for the corresponding D ‐aromatic amino acids. Such enantioselectivity only occurred in the gel state. No similar phenomenon could be observed in solution. This result suggested that, during the gel formation, the gelator molecules self‐assembled into ordered, chiral supramolecular structures and enhanced the enantiorecognition of the L ‐aromatic amino acids.     

One‐pot Chemoenzymatic Synthesis of Chiral 1,3‐Diols Using an Enantioselective Aldol Reaction with Chiral Zn2+ Complex Catalysts and Enzymatic Reduction Using Oxidoreductases with Cofactor Regeneration

We previously reported on enantioselective aldol reactions of acetone and some aldehydes catalyzed by chiral Zn²⁺ complexes of L ‐prolyl‐pendant [12]aneN₄ (L ‐ZnL¹) and L ‐valyl‐pendant [12]aneN₄ (L ‐ZnL²) in aqueous solution. Here, we report on the one‐pot chemoenzymatic synthesis of chiral 1,3‐diols in an aqueous solvent system at room temperature by a combination of enantioselective aldol reactions catalyzed by Zn²⁺ complexes of L ‐ and D ‐phenylalanyl‐pendant [12]aneN₄ (L ‐ZnL³ and D ‐ZnL³) and the successive enantioselective reduction of the aldol products using oxidoreductases with the regeneration of the NADH (reduced form of nicotinamine adenine dinucleotide) cofactor. The findings indicate that all four stereoisomers of 1,3‐diols can be produced by appropriate selection of a chiral Zn²⁺‐complex and an oxidoreductase commercially available from the “Chiralscreen OH” kit.     

5‐Carboxymethyl‐2‐(4‐methylthiophenyl)‐1,3,2‐dioxaborolan‐4‐one: synthesis,characterization and application in enantioselective reduction of ketones

The reaction of arylboronic acids with L ‐O‐benzoyl‐tartaric acid and D ,L ‐malic acid has been studied. The obtained (acyloxy)boranes are moderately stable in solution and decompose to give boroxines. 5‐Carboxymethyl‐2‐(4‐methylthiophenyl)‐1,3,2‐dioxaborolan‐4‐one was obtained in the reaction of 4‐methylthiophenylboronic acid with D ,L ‐malic acid and characterized by X‐ray structural analysis. The use of L ‐(−)‐malic acid afforded the optically pure product which can be used as the powerful chiral reagent in the enantioselective reduction of ketones. Copyright © 2011 John Wiley & Sons, Ltd.     

Enantioseparation of dansyl amino acids by ligand‐exchange capillary electrophoresis with zinc(II)‐L‐phenylalaninamide complex

A novel method of chiral ligand‐exchange CE was developed with L ‐amino acylamides as a chiral ligand and zinc(II) as a central ion. It has been demonstrated that these chiral complexes, such as Zn(II)‐L ‐alaninamide, Zn(II)‐L ‐prolinamide, and Zn(II)‐L ‐phenylalaninamide, are suitable for use as chiral selectors for the enantioseparation of either individual pair of or mixed dansyl amino acids. The optimal separation running buffer consisted of 5 mM ammonium acetate, 100 mM boric acid, 4 mM ZnSO₄·7 H₂O, and 8 mM L ‐amino acylamides at pH 8.2. The experiments showed that apart from the effect of the concentration of the complexes on the resolution and the migration time, the buffer pH also had a sharp influence on resolution. The employed chiral ligands exhibited different enantioselectivities and enantiomer migration orders. D ‐Amino acids migrate faster than L ‐amino acids when Zn(II)‐L ‐alaninamide and Zn(II)‐L ‐phenylalaninamide are used as chiral selectors, but it was observed that the migration order is reversed when Zn(II)‐L ‐prolinamide is used as the chiral selector. Furthermore, the amount of dansylated amino acids is found to be highly dependent on the labeling temperature.     

Chiral SiO2 and Ag@SiO2 Materials Templated by Complexes Consisting of Comblike Polyethyleneimine and Tartaric Acid

A facile avenue to fabricate micrometer‐sized chiral (L ‐, D ‐) and meso‐like (dl ‐) SiO₂ materials with unique structures by using crystalline complexes (cPEI/tart), composed of comblike polyethyleneimine (cPEI) and L ‐, D ‐, or dl ‐tartaric acid, respectively, as catalytic templates is reported. Interestingly, both chiral crystalline complexes appeared as regularly left‐ and right‐twisted bundle structures about 10 μm in length and about 5 μm in diameter, whereas the dl ‐form occurred as circular structures with about 10 μm diameter. Subsequently, SiO₂@cPEI/tart hybrids with high silica content (>55.0 wt %) were prepared by stirring a mixture containing tetramethoxysilane (TMOS) and the aggregates of the crystalline complexes in water. The chiral SiO₂ hybrids and calcined chiral SiO₂ showed very strong CD signals and a nanofiber‐based morphology on their surface, whereas dl ‐SiO₂ showed no CD activity and a nanosheet‐packed disklike shape. Furthermore, metallic silver nanoparticles (Ag NPs) were encapsulated in each silica hybrid to obtain chiral (D and L forms) and meso‐like (dl form) Ag@SiO₂ composites. Also, the reaction between L ‐cysteine (Lcys) and these Ag@SiO₂ composites was preliminarily investigated. Only chiral L ‐ and D ‐Ag@SiO₂ composites promoted the reaction between Lcys and Ag NPs to produce a molecular [Ag–Lcys]_n complex with remarkable exciton chirality, whereas the reaction hardly occurred in the case of meso‐like (dl ‐) Ag@SiO₂ composite.     

Self‐Assembled Ultralong Chiral Nanotubes and Tuning of Their Chirality Through the Mixing of Enantiomeric Components

Enantiomeric L ‐ or D ‐glutamic acid based lipids were designed and their self‐assembly was investigated. It was found that at a certain concentration, either L ‐ or D ‐enantiomeric derivatives could self‐assemble in absolute alcohol to form a white organogel, which was composed of ultralong nanotubes with an aspect ratio higher than 1000. Further investigations revealed that these nanotubes were in chiral forms. The chirality of the nanotubes was determined by that of the enantiomers employed. In addition, when D and L enantiomers were mixed in different ratios, the nanotube could be tuned consecutively from nanotubes with a helical seam to nanotwists, the chirality of which being determined by the excess enantiomer in the mixed systems. In the case of an equimolar mixture of the enantiomers, flat nanoplates instead of helical nanotubes or nanotwists were obtained. The FTIR vibrational data and XRD layer‐distance values showed a consecutive change as a function of the enantiomeric excess. It was further revealed that the slightly stronger interaction between D –L enantiomeric pairs than that between D –D or L –L pairs was responsible for the formation of the diverse self‐assembled nanostructures.     

Heart‐cutting 2D‐CE with on‐line preconcentration for the chiral analysis of native amino acids

The use of transient moving chemical reaction boundary (tMCRB) was investigated for the on‐line preconcentration of native amino acids in heart‐cutting 2D‐CE with multiple detection points using contactless conductivity detection. The tMCRB focusing was obtained by using ammonium formate (pH 8.56) as sample matrix and acetic acid (pH 2.3) as a BGE in the first dimension of the heart‐cutting 2D‐CE. Different experimental parameters such as the injected volume and the concentration in ammonium formate were optimized for improving the sensitivity of detection. A stacked fraction from the first dimension was selected, isolated in the capillary, and then separated in the second dimension in the presence of a chiral selector ((+)‐(18‐crown‐6)‐2,3,11,12‐tetracarboxylic acid). This on‐line tMCRB preconcentration coupled with heart‐cutting 2D‐CE was applied with success to the chiral separation of D ,L ‐phenylalanine, and D ,L ‐threonine in a mixture of 22 native amino acids. The sample mixture was diluted in 0.8 M of ammonium formate, and injected at a concentration of 2.5 μM for each enantiomer with a volume corresponding to 10% of the total capillary volume. An LOD (S/N=3) of 2 μM was determined for L ‐threonine.     

Pentopyranosyl Oligonucleotide Systems,Communication No. 10 , The α‐L‐Lyxopyranosyl‐(4′→2′)‐oligonucleotide System

To determine whether the remarkable chemical properties of the pyranosyl isomer of RNA as an informational Watson‐Crick base‐pairing system are unique to the pentopyranosyl‐(4′→2′)‐oligonucleotide isomer derived from the RNA‐building block D ‐ribose, studies on the entire family of diastereoisomeric pyranosyl‐(4′→2′)‐oligonucleotide systems deriving from D ‐ribose, L ‐lyxose, D ‐xylose, and L ‐arabinose were carried out. The result of these extended studies is unambiguous: not only pyranosyl‐RNA, but all members of the pentopyranosyl‐(4′→2′)‐oligonucleotide family are highly efficient Watson‐Crick base‐pairing systems. Their synthesis and pairing properties will be described in a series of publications in this journal. The present paper describes the α‐L ‐lyxopyranosyl‐(4′→2′)‐system.     

Determination of D,L‐serine in midbrain of Parkinson's disease mouse by capillary electrophoresis with in‐column light‐emitting diode induced fluorescence detection

A capillary electrophoresis method with in‐column light‐emitting diode induced fluorescence detection is described for simultaneous determination of D ,L ‐serine in the midbrain of a Parkinson's disease mouse. D ,L ‐Serine was derivatized with fluorescein isothiocyanate, and chiral separation and determination of D ,L ‐serine derivatives were performed on a laboratory‐built capillary electrophoresis system with in‐column light‐emitting diode induced fluorescence detector using γ‐cyclodextrin as chiral selector. Using this method, the levels of D ‐ and L ‐serine in the midbrains of Parkinson's disease mice were determined. When compared to controls, the levels of D ‐ and L ‐serine showed significant differences. The result suggested that the biosynthesis and the transportation of endogenous D ,L ‐serine may participate in Parkinson's disease pathogenesis.     

Chemical Etiology of Nucleic Acid Structure: The Pentulofuranosyl Oligonucleotide Systems: The (1′→3′)‐β‐L‐Ribulo, (4′→3′)‐α‐L‐Xylulo,and (1′→3′)‐α‐L‐Xylulo Nucleic Acids

Under potentially prebiotic scenarios, ribose (pentose), the component of RNA is formed in meager amounts, as opposed to ribulose and xylulose (pentuloses). Consequently, replacement of ribose in RNA, with pentulose sugars, gives rise to prospective oligonucleotide candidates that are potentially prebiotic structural variants of RNA that could be formed by the same type of chemical pathways that gave rise to RNA from ribose. The potentially natural alternative (1′→3′)‐ribulo oligonucleotides and (4′→3′)‐ and (1′→3′)‐xylulo oligonucleotides consisting of adenine and thymine were synthesized and found to exhibit no self‐pairing or cross‐pairing with RNA. This signifies that even though pentulose sugars may have been abundant in a prebiotic scenario, the pentulose nucleic acids (NAs), if and when formed, would not have been competitors of RNA, or interfered with the emergence of RNA as a functional informational system. The reason for the lack of base pairing in pentulose NA highlights the contrasting and central role played by the furanosyl ring in RNA and pentulose NA, enabling and optimizing the base pairing in RNA, while impeding it in pentulose NA.     

Cyclic polypeptides by thermal polymerization of α‐amino acid N‐carboxyanhydrides

The NCAs of the following five amino acids were polymerized in bulk at 120 °C without addition of a catalyst or initiator: sarcosine (Sar), L ‐alanine (L ‐Ala), D ,L ‐phenylalanine (D ,L ‐Phe), D ,L ‐leucine (D ,L ‐Leu) and D ,L ‐valine (D,L ‐Val). The virgin reaction products were characterized by viscosity measurements ¹³C NMR spectroscopy and MALDI‐TOF mass spectrometry. In addition to numerous low molar mass byproducts cyclic polypeptides were formed as the main reaction products in the mass range above 800 Da. Two types of cyclic oligo‐ and polypeptides were detected in all cases with exception of sarcosine NCA, which only yielded one class of cyclic polypeptides. The efficient formation of cyclic oligo‐ and polypeptides explains why high molar mass polymers cannot be obtained by thermal polymerizations of α‐amino acid NCAs. Various polymerization mechanisms were discussed. © 2008 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 46: 4012–4020, 2008     

Amphiphilic Schiff Base Organogels: Metal‐Ion‐Mediated Chiral Twists and Chiral Recognition

New amphiphilic gelators that contained both Schiff base and L ‐glutamide moieties, abbreviated as o‐SLG and p‐SLG, were synthesized and their self‐assembly in various organic solvents in the absence and presence of metal ions was investigated. Gelation test revealed that o‐SLG formed a thermotropic gel in many organic solvents, whilst p‐SLG did not. When metal ions, such as Cu²⁺, Zn²⁺, Mg²⁺, Ni²⁺, were added, different behaviors were observed. The addition of Cu²⁺ induced p‐SLG to from an organogel. In the case of o‐SLG, the addition of Cu²⁺ and Mg²⁺ ions maintained the gelating ability of the compound, whilst Zn²⁺ and Ni²⁺ ions destroyed the gel. In addition, the introduction of Cu²⁺ ions caused the nanofiber gel to perform a chiral twist, whilst the Mg²⁺ ions enhanced the fluorescence of the gel. More interestingly, the Mg²⁺‐ion‐mediated organogel showed differences in the fluorescence quenching by D ‐ and L ‐tartaric acid, thus showing a chiral recognition ability.     

Imidazole‐initiated polymerizations of α‐amino acid N‐carboxyanhydrides – simultaneous chain‐growth and step‐growth polymerization

The N‐carboxyanhydrides (NCAs) of sarcosine (Sar), D ,L ‐leucine (D ,L ‐Leu), D ,L ‐phenylalanine (D ,L ‐Phe), and L ‐alanine (L ‐Ala) were polymerized in dioxane. Imidazole served as initiator and the NCA/initiator ratio was varied from 1/1 to 40/1. The isolated polypeptides were characterized by ¹H NMR spectroscopy, by MALDI‐TOF mass spectrometry, by viscosity measurements, and by SEC measurements in the case of poly(sarcosine). Cyclic oligopeptides were found in all reaction products and in the case of polySar, poly(D ,L ‐Leu), and poly(D ,L ‐Phe) the cycles were the main products. In the case of poly(L ‐Ala), rapid precipitation of β‐sheet lamellaes prevented efficient cyclizations and stabilized imidazolide endgroups. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 5690–5698, 2005     

Studies on the Stereoselective Synthesis of Deuterated D‐Ribose Derivatives

In view of the importance of the site‐specific substitution of the H‐atom by its stable isotope ²H in a stereoselective/stereospecific manner at the pentose sugar residue, decreasing the spectral overcrowding in various regions of 1D and 2D homo‐ and heteronuclear correlation spectra of oligo‐DNA and ‐RNA, there is always a need for the development of new methods for the incorporation of ²H at different sites of a ribose. High‐yielding multistep syntheses of C(2)‐, and (5R)‐ and (5S)‐3,5‐deuterated ribose derivatives have been envisaged for the application of site‐specific incorporation of multilabeled nucleosides into oligomers to facilitate their structure elucidation by NMR spectroscopy. All syntheses started from D ‐glucose after proper derivatization. In the case of C(2), >97 atom‐% isotope was incorporated, employing an inversion of the configuration at C(2) as the key reaction. For C(5), two different routes were envisaged: on the one hand, deuterated achiral reagent was treated with a conformationally locked sugar moiety 15 , while, on the other, chiral protonated sources were used to transfer the H‐atom to a C(5)‐deuterated aldehyde 18 . In all cases, enantiomeric and isotopic purities were found to be as high as >97% as determined by NMR spectroscopy.     

Chiral polyamides consisting of N‐α‐benzoyl‐L‐glutamic acid as a diacid component

Novel polyamide with chiral environment was obtained from aromatic diamine, 4,4′‐diaminodiphenylmethane (DADPM), and N‐α‐protected L ‐glutamic acid, N‐α‐benzoyl‐L ‐glutamic acid (Benzoyl‐L ‐Glu‐OH). The optical rotation ([α]_D ) of the polyamide was determined to be 3.6° (c = 1.00 g/dL in DMF), implying that the optically active polyamide was obtained. The present polyamide gave a durable self‐standing membrane. The membrane selectively incorporated the D ‐isomer of Ac‐Trp from racemic mixture of Ac‐Trp. The adsorption selectivity toward Ac‐D ‐Trp was determined to be 1.95. It showed chiral separation ability by adopting potential difference as a driving force for membrane transport. The permselectivity was dependent on the potential difference, and at the applied potential difference of 3.0 V, the membrane selectively transported Ac‐D ‐Trp and the permselectivity toward Ac‐D ‐Trp was determined to be 1.84, which was close to the adsorption selectivity of 1.95. Contrary to this, the membrane showed opposite permselectivity at the applied potential difference of 2.0 V and the permselectivity toward the L ‐isomer reached 2.48. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 2530–2538, 2009     

Generation of well‐defined clickable glycopolymers from aqueous RAFT polymerization of isomaltulose‐derived acrylamides

Original carbohydrate‐based acrylamides bearing one azide group in C‐2 or C‐6 position namely, 2‐[(2‐deoxy‐2‐azido‐α‐D ‐mannopyranosyloxy)ethanamido]‐ethyl acrylamide (II) and 2‐[(6‐deoxy‐6‐azido‐α‐D ‐glucopyranosyloxy)ethanamido]‐ethyl acrylamide (III), and their azide‐free analogue, 2‐[(α‐D ‐glucopyranosyloxy)ethanamido]‐ethyl acrylamide (I), have been designed. Whereas the reversible addition fragmentation chain transfer (RAFT) process ensured the preparation of well‐defined glycopolymers from I, the polymerization of monomers II and III proved to be challenging at temperatures compatible with a thermally initiated radical process, due to the presumed concomitant 1,3‐cycloaddition reactions between the azide and the acrylamide moieties. In contrast to III, for which no polymer could be obtained under any conditions, performing the RAFT polymerization of II at 30 °C clearly favored the radical polymerization and conferred a controlled character to the process, affording well‐defined azide‐functionalized glycopolymers and block copolymers. The presence of numerous azide moieties was finally exploited to introduce carbohydrates onto the glycopolymer backbone through copper catalyzed azide‐alkyne cycloaddition. © 2011 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011     

Preparation of chiral amino acid materials and the study of their interactions with 1,1‐Bi‐2‐naphthol

The amino acid tryptophan has been converted into acrylamide monomers using L /D ‐tryptophan methyl ester forming the enantiopure chiral monomers. Attempts were made to polymerize these monomers via reversible addition fragmentation chain transfer (RAFT) polymerization to form poly(tryptophan). Unfortunately, this proved difficult, and instead, a postpolymerization modification route was used by first synthesizing poly(pentafluorophenyl acrylate) via RAFT, which was then substituted with L ‐tryptophan methyl ester to give poly(L ‐tryptophan). The interactions of the newly synthesized tryptophan monomers, as well as previously reported phenylalanine monomers, were studied in the presence of rac‐BINOL. It has been shown that the enantiomers of tryptophan have a stronger interaction with BINOL than phenylalanine and this has been attributed to the larger π system on the side chain. By monitoring the shifts and splitting of the phenolic protons of BINOL, it has been observed that S‐BINOL interacts more favorably with L ‐monomer enantiomers and R‐BINOL with D ‐monomer enantiomers. Similar interactions have also been seen with poly(phenylalanine) and the newly synthesized poly(tryptophan) materials. © 2012 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2012