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Since our work on corrin synthesis was intended to be a model study for the construction of the ligand system of vitamin B12 (cf. Part I of this series), the choice of an A/D component that would contain an angular Me group at the junction between rings A and D seemed crucial. Such a Me group was expected to direct (through its steric impact) a regioselective functionalization of the two carbonyl groups of a corresponding dilactam structure that appeared to be the obvious type of intermediate in the construction of an A/D component. The target A/D structure envisaged originally was the methyl ester derivative 1a (cf. Fig. 1). However, observations in an early phase of our work made it clear that we better aim at the nitrile derivative 1b, instead of the corresponding methyl ester. Nitrile 1b was in fact synthesized, but not used as A/D component, because, on the way to its synthesis, the opportunity emerged to prepare structure 2. As A/D component, 2 differs from 1b by the isomeric positioning of the angular Me group, it could be prepared regio- as well as stereoselectively and, therefore, much more efficiently than 1b.

A definition of the scope of aromatic substrates that participate with catharanthine in an Fe(III)-mediated coupling reaction, an examination of the key structural features of catharanthine required for participation in the reaction, and the development of a generalized indole functionalization reaction that bears little structural relationship to catharanthine itself are detailed. In addition to providing insights into the mechanism of the Fe(III)-mediated coupling reaction of catharanthine with vindoline suggesting the reaction conducted in acidic aqueous buffer may be radical mediated, the studies provide new opportunities for the preparation of previously inaccessible vinblastine analogs and define powerful new methodology for the synthesis of indole-containing natural and unnatural products.

“Wir werden es nie wissen konnen” ist ein Truismus, der zu Resignation gegenuber jeglicher experimenteller Investition in eine Suche nach der Chemie der Entstehung des Lebens verfuhrt. Doch widerspricht solche Resignation radikal der Herausforderung, die der Chemie als Naturwissenschaft auferlegt ist. Ungeachtet der Prognose, wonach der kurzeste Weg zum Verstandnis der Metamorphose des Chemischen ins Biologische uber die experimentelle Modellierung “kunstlichen chemischen Lebens” fuhrt, wird die naturwissenschaftliche Suche nach dem von der Natur begangenen Weg der Entstehung des Lebens, das wir kennen, wohl nie wirklich enden. Denn sie ist Teil der Suche nach unserem eigenen Ursprung.

"Back of the envelope" methods have their place in experimental chemical research; they are effective mediators in the generation of research ideas, for instance, the design of molecular structures. Their qualitative character is part of their strength, rather than a drawback for the role they have to play. Qualitative conformational analysis of oligonucleotide and other oligomer systems on the level of idealized conformations is one such method; it has played a helpful role in our work on the chemical etiology of nucleic acid structure. This article, while giving a short overview of that work, shows how.

What a relief! In 1955 the principle of strain release was put forward to explain the differing reactivity of axial and equitorial alcohols during oxidation. Our findings suggest that this same rationale may account for the differing rates of activation between axial and equitorial C–H bonds in C–H activation processes. In conjunction with steric and electronic considerations, strain-release can be used to qualitatively predict relative rates and site specificity of C–H activation in complex settings.

A central postulate of contemporary natural science states that life emerged on Earth (or elsewhere) through a transition of chemical matter from non-living to living. The transition is seen as a contingent consequence of the second law of thermodynamics and the chemical properties of matter by one group of scientists, and as an imperative of that law and those properties according to the belief of others. Chemical matter is postulated to have been capable of organizing itself out of disorder by channeling exergonic geochemical reactions into reaction networks that had a dynamic structure with kinetic (as opposed to thermodynamic) stability and were driven by autocatalytic molecular replication cycles. The postulate implicates that such chemical systems eventually became self-sustaining (capable of exploiting environmental sources for reconstituting itself), adaptive (capable of reacting to physical or chemical changes in the environment such that survival as a system is maintained) and – by operating in compartments – capable of evolving. From this perspective, life’s origin is seen as a seamless transition from self-ordering chemical reactions to self-sustaining chemical systems that are capable of Darwinian evolution [1]. Figure 1 delineates – in terms of a ‘conceptual cartoon’ – such a programmatic view in more detail. Evidence from paleontology, biology, geology and planetary science posits the appearance of life on Earth into a period of 3 to 4 billion years ago. Whereas the course of biological evolution is documented by a wealth of fossils of extinct organisms and, more recently, by information from comparative analysis of the genomes of biological species, there are no ‘fossils’ that would reliably document the nature of the molecules that were involved in the chemical processes at the dawn of life. We do not know whether at the beginning there existed a multitude of different life forms from one of which the one we know today has derived, neither do we know whether the type of molecules and chemical processes on which such 07_Eschenmoser(OK) Gabri_dis:Layout 1 25/09/09 11:07 Pagina 181

The N,O-acetal and N,O-ketal derivatives (oxazolidinones) formed from proline, and aldehydes or ketones are well-known today, and they are detectable in reaction mixtures involving proline catalysis, where they have been considered ‘parasitic dead ends’. We disclose results of experiments performed in the early 1970's, and we describe more recent findings about the isolation, characterization, and reactions of the oxazolidinone derived from proline and cyclohexanone. This oxazolidinone reacts (THF, room temperature) with the electrophiles β-nitrostyrene and chloral (=trichloroacetaldehyde), to give the Michael and aldol adduct, respectively, after aqueous workup (Scheme 5). The reactions occur even at −75° when catalyzed with bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or EtN(i-Pr)2 (DIPEA) (10%; Table 1). It is shown by NMR (Figs. 1 and 3) and IR analysis (Figs. 2 and 4) that the primarily detectable product (before hydrolysis) of the reaction with the nitro-olefin is again an oxazolidinone. When dissolved in hydroxylic solvents such as MeOH, ‘hexafluoroisopropanol’ ((CF3)2CHOH; HFIP), AcOH, CF3COOH, or in LiBr-saturated THF, the ring of the oxazolidinone from cyclohexanone and proline opens up to the corresponding iminium ion (Tables 2–4), and when treated with strong bases such as DBU (in (D8)THF) the enamino-carboxylate derived from proline and cyclohexanone is formed (Scheme 8). Thus, the two hitherto putative participants (iminium ion and enamine) of the catalytic cycle (Scheme 9) have been characterized for the first time. The commonly accepted mechanism of the stereoselective C,C- or C,X-bond-forming step (i.e., A–D) of this cycle is discussed and challenged by thoughts about an alternative model with a pivotal role of oxazolidinones in the regio- and diastereoselective formation of the intermediate enamino acid (by elimination) and in the subsequent reaction with an electrophile (by trans-addition with lactonization; Schemes 11–14). The stereochemical bias between endo- and exo-space of the bicyclo[3.3.0]octane-type oxazolidinone structure (Figs. 5 and 6) is considered to possibly be decisive for the stereochemical course of events. Finally, the remarkable consistency, with which the diastereotopic Re-face of the double bond of pyrrolidino-enamines (derived from proline) is attacked by electrophiles (Schemes 1 and 15), and the likewise consistent reversal to the Si-face with bulky (Aryl)2C-substituents on the pyrrolidine ring (Scheme 16) are discussed by invoking stereoelectronic assistance from the lone pair of pyramidalized enamine N-atoms.

An experimental rationalization of the structure type encountered in DNA and RNA by systematically investigating the chemical and physical properties of alternative nucleic acids has identified systems with a variety of sugar-phosphate backbones that are capable of Watson-Crick base pairing and in some cases cross-pairing with the natural nucleic acids. The earliest among the model systems tested to date, (4' --> 6')-linked oligo(2',3'-dideoxy-beta-d-glucopyranosyl)nucleotides or homo-DNA, shows stable self-pairing, but the pairing rules for the four natural bases are not the same as those in DNA. However, a complete interpretation and understanding of the properties of the hexapyranosyl (4' --> 6') family of nucleic acids has been impeded until now by the lack of detailed 3D-structural data. We have determined the crystal structure of a homo-DNA octamer. It reveals a weakly twisted right-handed duplex with a strong inclination between the hexose-phosphate backbones and base-pair axes, and highly irregular values for helical rise and twist at individual base steps. The structure allows a rationalization of the inability of allo-, altro-, and glucopyranosyl-based oligonucleotides to form stable pairing systems.

An X-ray structure analysis of the title compound reveals that this purinoid exists in the crystal as two tautomers which interact with each other in the mode of a reverse-Watson–Crick base pair.

Regioselective Mannich-type C-nucleosidations of pyrroline derivatives 3 and 8 with 7-carba-purines and 4-aminopyrimidines occur under mild conditions to afford C(8)- and C(5)-azanucleosides, respectively.

C-Nucleosidation with cyclic iminium salts occurring under mild reaction conditions and affording C-nucleosides that are isosteric with N-nucleosides of natural purines is shown to be a consistent property of the entire family of 2,6-(oxo or amino)-disubstituted 5,8-diaza-7,9-dicarba-purines.

As part of a project that aims at screening TNA-related oligonucleotide systems in which threose backbone units may have some or all of their oxygen functions replaced by nitrogen, two TNA analogs containing (2'NH)- and (3'NH)-phosphoramidate groups, respectively, in place of phosphodiester groups were synthesized. They show base-pairing properties that are very similar to those of TNA itself. We also synthesized 2',3'-diamino analogs of alpha-L-threofuranosyl mononucleosides, yet attempts to convert them to TNA analogs containing phosphodiamidate linker groups were not successful. Such 2',3'-diamino derivatives of threofuranosyl nucleosides may be of interest, however, as building blocks of TNA analogs that contain non-phosphorous linker groups.

Anfinsen showed that a protein's fold is specified by its sequence. Although it is clear why mutant proteins form amyloid, it is harder to rationalize why a wild-type protein adopts a native conformation in most individuals, but it misfolds in a minority of others, in what should be a common extracellular environment. This discrepancy suggests that another event likely triggers misfolding in sporadic amyloid disease. One possibility is that an abnormal metabolite, generated only in some individuals, covalently modifies the protein or peptide and causes it to misfold, but evidence for this is sparse. Candidate metabolites are suggested by the recently appreciated links between Alzheimer's disease (AD) and atherosclerosis, known chronic inflammatory metabolites, and the newly discovered generation of ozone during inflammation. Here we report detection of cholesterol ozonolysis products in human brains. These products and a related, lipid-derived aldehyde covalently modify Aβ, dramatically accelerating its amyloidogenesis in vitro , providing a possible chemical link between hypercholesterolemia, inflammation, atherosclerosis, and sporadic AD.

Pyranosyl-RNA (qp-RNAq) is an oligonucleotide system isomeric to natural RNA and composed of the very same building blocks as RNA. Its generational, chem., and informational properties are deemed to be those of an alternative nucleic acid system that could have been a candidate in Nature's evolutionary choice of the mol. basis of genetic function. We consider the study of the chem. of p-RNA as etiol. relevant in the sense that knowledge of its structural, chem., and informational properties on the chem. level offers both a perspective and ref. points for the recognition of specific structural assets of the RNA structure that made it the (supposedly) superior system among possible alternatives and, therefore, the system that became part of biol. as we know it today. The paper describes the chem. synthesis of b-D- (and -L)-ribopyranosyl-(4'->2')-oligonucleotide sequences, presents a resume of their structural and chem. properties, and cautiously discusses what we may and may not have learned from the pyranosyl isomer of RNA with respect to the conundrum of RNA's origin. [on SciFinder (R)]

Here, we report evidence for the production of ozone in human disease. Signature products unique to cholesterol ozonolysis are present within atherosclerotic tissue at the time of carotid endarterectomy, suggesting that ozone production occurred during lesion development. Furthermore, advanced atherosclerotic plaques generate ozone when the leukocytes within the diseased arteries are activated in vitro. The steroids produced by cholesterol ozonolysis cause effects that are thought to be critical to the pathogenesis of atherosclerosis, including cytotoxicity, lipid-loading in macrophages, and deformation of the apolipoprotein B-100 secondary structure. We propose the trivial designation “atheronals” for this previously unrecognized class of steroids.

The title compound, a constitutional isomer of the natural nucleobase 2,6-diaminopurine, undergoes regioselective electrophilic substitutions at carbon C-9.

Endocyclic iminium ions derived from l-4-amino-threose derivatives smoothly react with 2,6-diamino-5,8-diaza-7,9-dicarba-purine to give corresponding C(9)-nucleosides in high yields.

Among the members of a family of diastereoisomeric pentopyranosyl-(4′2′)-oligonucleotide systems derived from D-ribose, D-xylose, L-lyxose, and L-arabinose, the α-arabinopyranosyl system shows by far the strongest WatsonCrick base pairing. The system is, in fact, one of the strongest oligonucleotide-type base-pairing systems known. It undergoes efficient cross-pairing with all the other members of the pentopyranosyl family, but not with RNA and DNA. The paper describes the synthesis and pairing of the properties of α-L-arabinopyranosyl-(4′2′)-oligonucleotides.

Recent work in our laboratory showed that products formed by the antibody-catalyzed water-oxidation pathway can kill bacteria. Dihydrogen peroxide, the end product of this pathway, was found to be necessary, but not sufficient, for the observed efficiency of bacterial killing. The search for further bactericidal agents that might be formed along the pathway led to the recognition of an oxidant that, in its interaction with chemical probes, showed the chemical signature of ozone. Here we report that the antibody-catalyzed water-oxidation process is capable of regioselectively converting antibody-bound benzoic acid into para -hydroxy benzoic acid as well as regioselectively hydroxylating the 4-position of the phenyl ring of a single tryptophan residue located in the antibody molecule. We view the occurrence of these highly selective chemical reactions as evidence for the formation of a short-lived hydroxylating radical species within the antibody molecule. In line with our previously presented hypothesis according to which the singlet-oxygen ( 1 O * 2 ) induced antibody-catalyzed water-oxidation pathways proceeds via the formation of dihydrogen trioxide (H 2 O 3 ), we now consider the possibility that the hydroxylating species might be the hydrotrioxy radical HO \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} \begin{equation*}{\mathrm{_{_{3}}^{{\bullet}}}}\end{equation*}\end{document} , and we point to the remarkable potential of this either H 2 O 3 - or O 3 -derivable species to act as a masked hydroxyl radical (HO • ) in a biological environment.

Our studies of α-L-Threofuranosyl-(3′→2′)-oligonucleotides (‘TNA') are part of a systematic experimental inquiry into the base-pairing properties of potentially natural nucleic acid alternatives taken from RNA's close structural neighborhood. TNA is an efficient Watson-Crick base-pairing system and has the capability of informational cross-pairing with both RNA and DNA. This property, together with the system's constitutional and (presumed) generational simplicity, warrants special scrutiny of TNA in the context of the search for chemical clues to RNA's origin.

The solution structure of the duplex formed by α-L-arabinopyranosyl-(4′2′)-(CGAATTCG) was studied by NMR. The resonances of all H-, P- and most C-atoms could be assigned. Dihedral angles and distance estimates derived from coupling constants and NOESY spectra were used as restraints in a simulated annealing calculation, which generated a well-defined bundle of structures for the six innermost nucleotide pairs. The essential features of the resulting structures are an antiparallel, WatsonCrick-paired duplex with a strong backbone inclination of ca. −50° and, therefore, predominant interstrand base stacking. The very similar inclination and rise parameters of arabinopyranosyl-(4′2′)-oligonucleotides and p-RNA explain why these two pentapyranosyl isomers are able to cross-pair.

Replacement of adenine by 2,6-diaminopurinetwo nucleobases to be considered equivalent from an etiological point of viewstrongly enhances the stability of TNA/TNA, TNA/RNA, or TNA/DNA duplexes and efficiently accelerates template-directed ligation of TNA ligands.

(3‘NH)- and (2‘NH)-TNA, two isomeric phosphoramidate analogues of TNA (α-threofuranosyl-(3‘→2‘) oligonucleotides), are shown to be efficient Watson−Crick base-pairing systems and to undergo intersystem cross-pairing with TNA, RNA, and DNA.

Recently we reported that antibodies can generate hydrogen peroxide (H 2 O 2 ) from singlet molecular oxygen ( 1 O 2 *). We now show that this process is catalytic, and we identify the electron source for a quasi-unlimited generation of H 2 O 2 . Antibodies produce up to 500 mole equivalents of H 2 O 2 from 1 O 2 *, without a reduction in rate, and we have excluded metals or Cl – as the electron source. On the basis of isotope incorporation experiments and kinetic data, we propose that antibodies use H 2 O as an electron source, facilitating its addition to 1 O 2 * to form H 2 O 3 as the first intermediate in a reaction cascade that eventually leads to H 2 O 2 . X-ray crystallographic studies with xenon point to putative conserved oxygen binding sites within the antibody fold where this chemistry could be initiated. Our findings suggest a protective function of immunoglobulins against 1 O 2 * and raise the question of whether the need to detoxify 1 O 2 * has played a decisive role in the evolution of the immunoglobulin fold.

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.