Convergent Dendrons and Dendrimers: from Synthesis to Applications

Dendrimers in Supramolecular Chemistry: From Molecular Recognition to Self-Assembly.

The origins of our nearly ten-year research program of chemical and biological investigations into peptides based on homologated proteinogenic amino acids are described. The road from the biopolymer poly[ethyl (R)-3-hydroxybutanoate] to the beta-peptides was primarily a step from organic synthesis methodology (the preparation of enantiomerically pure compounds (EPCs)) to supramolecular chemistry (higher-order structures maintained through non-covalent interactions). The performing of biochemical and biological tests on the beta- and gamma-peptides, which differ from natural peptides/proteins by a single or two additional CH(2) groups per amino acid, then led into bioorganic chemistry and medicinal chemistry. The individual chapters of this review article begin with descriptions of work on beta-amino acids, beta-peptides, and polymers (Nylon-3) that dates back to the 1960s, even to the times of Emil Fischer, but did not yield insights into structures or biological properties. The numerous, often highly physiologically active, or even toxic, natural products containing beta- and gamma-amino acid moieties are then presented. Chapters on the preparation of homologated amino acids with proteinogenic side chains, their coupling to provide the corresponding peptides, both in solution (including thioligation) and on the solid phase, their isolation by preparative HPLC, and their characterization by mass spectrometry (HR-MS and MS sequencing) follow. After that, their structures, predominantly determined by NMR spectroscopy in methanolic solution, are described: helices, pleated sheets, and turns, together with stack-, crankshaft-, paddlewheel-, and staircase-like patterns. The presence of the additional C--C bonds in the backbones of the new peptides did not give rise to a chaotic increase in their secondary structures as many protein specialists might have expected: while there are indeed more structure types than are observed in the alpha-peptide realm - three different helices (10/12-, 12-, and 14-helix) if we include oligomers of trans-2-aminocyclopentanecarboxylic acid, for example - the structures are already observable with chains made up of only four components, and, having now undergone a learning process, we are able to construct them by design. The structures of the shorter beta-peptides can also be reliably determined by molecular-dynamics calculations (in solution; GROMOS program package). Unlike in the case of the natural helices, these compounds' folding into secondary structures is not cooperative. In beta- and gamma-peptides, it is possible to introduce heteroatom substituents (such as halogen or OH) onto the backbones or to incorporate heteroatoms (NH, O) directly into the chain, and, thanks to this, it has been possible to study effects unobservable in the world of the alpha-peptides. Tests with proteolytic enzymes of all types (from mammals, microorganisms, yeasts) and in vivo examination (mice, rats, insects, plants) showed beta- and gamma-peptides to be completely stable towards proteolysis and, as demonstrated for two beta-peptides, extraordinarily stable towards metabolism, even when bearing functionalized side chains (such as those of Thr, Tyr, Trp, Lys, or Arg). The beta-peptides so far examined also normally display no or only very weak cytotoxic, antiproliferative, antimicrobial, hemolytic, immunogenic, or inflammatory properties either in cell cultures or in vivo. Even biological degradation by microbial colonies of the types found in sewage-treatment plants or in soil is very slow. That there are indeed interactions of beta- and gamma-peptides with biological systems, however, can be seen in the following findings: i) organ-specific distribution takes place after intravenous (i.v.) administration in rats, ii) transport through the intestines of rodents has been observed, iii) beta-peptides with positively charged side chains (Arg and Lys) settle on cell surfaces, are able to enter into mammalian cells (fibroplasts, keratinocytes, HeLa cells), and migrate into their cell nuclei (and nucleoli), and iv) in one case, it has already been established that a beta-peptide derivative can up- and down-regulate gene expression rates. Besides these less sharply definable interactions, it has also been possible to construct beta- and gamma-peptide agonists of naturally occurring peptide hormones, MHC-binding beta-peptides, or amphipathic beta-peptide inhibitors of membrane-bound proteins in a controlled fashion. Examples include somatostatin mimics and the suppression of cholesterol transport through the intestinal brush-border membrane (by the SR-BI-protein). The results so far obtained from investigations into peptides made up of homologues of the proteinogenic amino acids also represent a contribution to deepening of our knowledge of the natural peptides/proteins, while potential for biomedicinal application of this new class of substances has also been suggested.

The world of beta- and gamma-peptides comprised of homologated proteinogenic amino acids and other components.

Suprasupermolecules with Novel Properties: Metallodendrimers.

“Chiral carbanions”—that is, enentiomerically enriched lithium–carbanion pairs in which the carbanionic center carries the chiral information—were regarded until recently as “exotic species.” In the past ten years it has become clear that they can, in fact, play a meaningful role in enantioselective synthesis, since substitution for lithium occurs here stereospecifically, usually with retention of configuration. They are also more readily and commonly accessible than was originally assumed. The trick lies in the use of lithium cations with chiral ligands, whether in the form of alkyllithium species used as bases in kinetically controlled, enantiotopically discriminating deprotonation, or in thermodynamically controlled equilibration in configurationally labile epimeric ion pairs. The lupine alkaloid (−)-sparteine has shown itself admirably suited as a chiral bidentate ligand, and its efficiency and breadth of application are so far unsurpassed. This contribution constitutes an overview of the preparation of chiral reagents, convering primarily “umpoled” synthons such as homoenolates. 1-oxyalkanides with a broad pattern of substitution, and α-aminobenzyl anions.

Enantioselective Synthesis with Lithium/(−)-Sparteine Carbanion Pairs

In order to replace a substituent at a single stereogenic center of a chiral molecule without racemization, a temporary center of chirality is first generated diastereoselectively, the original tetragonal center is then trigonalized by removal of a substituent, a new ligand is introduced, again diastereoselectively, and finally, the temporary center is removed. By means of these four steps (the “Self-Regeneration of Stereocenters”, SRS), 2- and 3-amino-, hydroxy-, and sulfanylcarboxylic acids have been successfully alkylated with formation of tertiary carbon centers and without the use of a chiral auxiliary. Use of this methodology has allowed the potential of these inexpensive chiral building blocks to be expanded considerably. This article aims to demonstrate (using, in part, examples from natural product syntheses) that chiral heterocyclic acetals with enamine, enol ether, enolate, dienolate, enoate, radical, and acyliminium functionalities and also those that are potential reactants for Michael additions and pericyclic processes (for example, electron-rich and electronpoor dienophiles and dienes) are now easily accessible, more often than not, in both enantiomeric forms. Stereogenic nitrogen atoms of aziridines, boron atoms of cyclic or linear systems, and stereogenic planes of π-complexes can also be used as the temporary chirality element in other approaches to the realization of the SRS principle. Enantiomerically pure derivatives of, for example, glycine, hydroxy- and sulfanylacetic acid, 3-aminopropanoic acid, and 3-oxocarboxylic acids can be prepared by resolution of racemic mixtures via diastereoisomeric salts or by chromatography on a chiral column. Hence, the extensive reactivity of compounds developed to test the SRS principle and, above all, the outstanding stereoselectivities of the reactions can be put to good use even when no suitable chiral precursor is available—even though this amounts to an abandonment of the principle! The readily available 2-tert-butyl-1,3-imidazolidin-3-one, -oxazolid-in-5-one, -dioxin-3-one, and -hydropyrimidinone (all of which contain a single stereogenic center at the acetal C atom) can thus be used in the preparation of a vast range of 2-amino- and 3-hydroxycarboxylic acids, and no chiral auxiliary has to be removed or regenerated during these procedures. (One example is the synthesis of 4-fluoro-MeBmt, a derivative of the C9 amino acid found in cyclosporin.) In the final chapter we will discuss the most useful findings gained from investigations into both the self-regeneration of stereocenters and the use of chiral acetals in the synthesis of enantiomerically pure compounds (EPC synthesis): the formation and characteristics of complexes obtained from Li-enolates and other Li compounds with secondary amines; the application of α-alkoxy and α-amino-Li-alkoxides as in situ bases and sources of aldehydes in CC bond forming reactions with unstable enolates or nitronates; the significance of A1,3 effects on the stereochemical course of nucleophilic, radical, and electrophilic reactions of N-acylated heterocycles and homo- or heterocyclic carboxylic ester enolates; and the effects of the amide protecting group on the reactivity of neighboring centers and on the stereoselectivity of the reactions at those centers. At the end of this article we have included an appendix containing tables, which are intended to summarize all the examples known in as complete a fashion as possible.

Self-Regeneration of Stereocenters (SRS)—Applications, Limitations, and Abandonment of a Synthetic Principle†‡

Stereoselective synthesis of a c-glycosidic analog of n-glucoasparagine

Zum Ersatz eines Substituenten am einzigen stereogenen Zentrum eines chiralen Molekuls ohne Racemisierung wird zunachst diastereoselektiv ein Hilfschiralitatszentrum generiert, dann das ursprunglich vorhandene tetragonale Zentrum durch Entfernen eines Substituenten trigonalisiert und – wiederum diastereoselektiv – ein neuer Ligand eingefuhrt, worauf das temporare Zentrum wieder entfernt wird. Durch diese vier Schritte gelingt es, ohne chirale Hilfsstoffe in Anspruch zu nehmen (unter «Selbstregeneration des Stereozentrums», SRS), 2- und 3-Amino-, -Hydroxy- und -Sulfanylcarbonsauren unter Bildung tertiarer Kohlenstoffzentren zu alkylieren und damit das Potential dieser wohlfeilen chiralen Synthesebausteine betrachtlich zu erweitern. Es wird – auch am Beispiel von Naturstoffsynthesen – gezeigt, das auf diese Weise heterocyclische Acetale mit Enamin-, Enolether-, Enolat-, Dienolat-, Enoat-, Radikal- und Acyliminium-Reaktivitat sowie Reaktanten fur Michael-Additionen und fur pericyclische Prozesse (beispielsweise elektronenreiche und elektronenarme Dienophile und Diene), gewohnlich in beiden enantiomeren Formen, zuganglich sind. Bei anderen Wegen zur Realisierung des SRS-Prinzips dienen stereogene Stickstoffatome von Aziridinen, Boratome in cyclischen und offenkettigen Systemen oder auch stereogene Ebenen vor π-Komplexen als Hilfschiralitatselemente. Um die hohen Reaktivitaten der fur die SRS entwickelten Verbindungen und vor allem die hervor ragenden Stereoselektivitaten der Reaktionen auch dann nutzbar zu machen, wenn es keine geeigneten chiralen Vorstufen gibt, werden – unter Preisgabe des Prinzips!–enantiomerenreine Derivate, z. B. von Glycin, von Hydroxy- und Sulfanylessigsaure, von 3-Aminopropionsaure oder von 3-Oxocarbonsauren durch Racematspaltung uber diastereomere Salze oder durch Chromatographie an chiralen Saulen hergestellt. So verfugbare 2-tert-Butyl-1,3-imidazolidin-3-one, -oxazolidin-5-one, -dioxin-3-one oder -hydropyrimidinone mit nur einem stereogenen Zentrum – am Acetal-C-Atom – dienen zur Herstellung fast beliebiger 2-Amino- oder 3-Hydroxycarbonsauren, wobei kein chiraler Hilfsstoff abgetrennt und zuruckgewonnen werden mus; ein Beispiel ist die Synthese von 4-Fluor-Me Bmt, einem Derivat der C9-Aminosaure aus Cyclosporin. Im abschliesenden Kapitel werden nutzliche Erkenntnisse besprochen, die im Laufe der Untersuchungen uber die Selbstregeneration von Stereozentren und uber chirale Acetale in der Synthese enantiomerenreiner Verbindungen (EPC-Synthese) gewonnen worden sind: die Bildung und Eigenschaften von Komplexen aus Li-Enolaten oder anderen Li-Verbindungen und sekundaren Aminen, die Verwendung von α-Alkoxy- und α-Amino-Li-Alkoholaten als Insitu-Basen und Quellen fur Aldehyde zur C-C-Verknupfung mit instabilen Enolaten oder Nitronaten, die Bedeutung des A1,3-Effektes fur den stereochemischen Verlauf von nucleophilen, radikalischen sowie elektrophilen Reaktionen N-acylierter Heterocyclen und homo- oder heterocyclischer Carbonsaureester-Enolate sowie die Einflusse von Amid-Schutzgruppen auf die Reaktivitat benachbarter Zentren und auf die Stereoselektivitat der Reaktionen an diesen Zentren. Am Ende des Beitrags befindet sich ein Anhang mit Tabellen, die eine weitgehend vollstandige Sammlung von Beispielen enthalten.

Die Selbstregeneration von Stereozentren (SRS) — Anwendungen, Grenzen und Preisgabe eines Syntheseprinzips

The synthesis of C-glycosidic analogues 15–22 of N4-(2-acetamido-2-deoxy-β-D-glucopyranosyl)-L-asparagine (Asn(N4GlcNAc)) possessing a reversed amide bond as an isosteric replacement of the N-glycosidic linkage is presented. The peptide cyclo(-D-Pro-Phe-Ala-CGaa-Phe-Phe-) (CGaa = C-glycosylated amino acid; 24) was prepared to demonstrate that 3-[(3-acetamido-2,6-anhydro-4,5,7-tri-O-benzyl-3-deoxy-β-D-glycero-D-guloheptonoyl)amino]-2-[(9H-fluoren-9-yloxycarbonyl)amino]propanoic acid (22) can be used in solid-phase peptide synthesis. The conformation of 24 was determined by NMR and molecular-dynamics (MD) techniques. Evidence is provided that the CGaa side chain interacts with the peptide backbone. The different C-glycosylated amino acids 15–21 were prepared by coupling 3-acetamido-2,6-anhydro-4,5,7-tri-O-benzyl-3-deoxy-β-D-glycero-D-gulo-heptonic acid (4) with diamino-acid derivatives 8–14 in 83–96% yield. The synthesis of 4 was performed from 2-(acetamido-3,4,6-tri-O-benzyl-2-deoxy-β-D-glucopyranosyl) tributylstannane (2) by treatment with BuLi and CO2 in 83% yield. Similarly, propyl isocyanat yielded the glycoheptonamide 7 in 52% from 2. Compound 2 was obtained from 2-acetamido-3,4,6-tri-O-benzyl-2-deoxy-D-glucopyranose (1) by chlorination and addition of tributyltinlithium in 74% yield. A procedure for a multigram-scale synthesis of 1 is given.

C‐Glycoside Analogues of N4‐(2‐Acetamido‐2‐deoxy‐β‐D‐glucopyranosyl)‐L‐asparagine: Synthesis and conformational analysis of a cyclic C‐glycopeptide

Stereoselective Synthesis of a C‐Glycosidic Analogue of N‐ Glucoasparagine

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