Till Opatz

Carbohydrates as Multifunctional Chiral Scaffolds in Combinatorial Synthesis

Four orthogonally stable protecting groups and a selectively cleavable anchor that are stable under basic conditions are required in order that carbohydrates can be employed as chiral polyfunctional scaffolds in combinatorial solid-phase syntheses of high diversity. The schematic representation shows the combinatorial synthesis with a carbohydrate scaffold (SG=protecting group, A=anchor, P=polymer carrier), which proceeds by sequential selective deprotection, functionalization, washing of the solid phase, and cleavage of the anchor.

Modular Synthesis of Tetrasubstituted Imidazoles and Trisubstituted Oxazoles by Aldimine Cross‐Coupling

Due to their widespread application in chemistry and technology, and their presence as partial structures in many natural products, imidazoles represent an important class of heterocycles. Whereas the unsubstituted parent compound serves as a nucleophilic catalyst or corrosion inhibitor, its derivatives exhibit a wide range of biological activities. For example, anti-inflammatory, antibacterial, antimycotic, as well as cytostatic imidazoles have been described. Imidazolium salts can be used as ionic liquids or as precursors of versatile N-heterocyclic carbenes. Commonly used methods for the construction of the imidazole ring include cyclocondensation reactions between a-diketones, a-hydroxy ketones, a-haloketones, or a-aminoketones and formamide (Bredereck synthesis), the reaction of a-diketones with aldehydes and ammonia according to Japp, Robinson, and Radziszewski and the reaction of a-haloketones with amidines. The formal cycloaddition of tosylmethyl isocyanide (TosMIC) and its substituted derivatives to aldimines (van Leusen reaction) is a less frequently encountered method that involves the formation of the C4 C5 bond. Since C C-bond formations that furnish 1,2disubstituted products require the use of a reactant with reversed polarity, an umpoled imine should be a suitable starting material. Our work on the 1,2-addition of readily available deprotonated N-monosubstituted a-aminonitriles to aldimines in a one-pot cross-coupling sequence gives access to isomerically pure tetrasubstituted 1,2-diamines and 1,2-diimines. The use of N-acylimines (instead of aldimines devoid of acceptor groups) should, in analogy, lead to a-acylaminoimines, which contain the ring-opened skeleton of the imidazoles (Scheme 1).

Synthesis of Lamellarin U and Lamellarin G Trimethyl Ether by Alkylation of a Deprotonated α-Aminonitrile

1,2,3,4-Tetrahydroisoquinoline-1-carbonitriles can serve as starting materials for the one-pot synthesis of 5,6-dihydropyrrolo[2,1 a]isoquinolines and 1-benzyl-3,4-dihydroisoquinolines. The latter compounds were transformed to lamellarin G trimethyl ether and lamellarin U in short reaction sequences. This method allows the introduction of acid-sensitive protecting groups for the phenolic hydroxy functions which would be cleaved under the harsh conditions of the classical Bischler-Napieralski reaction.

Sfp-Type 4′-Phosphopantetheinyl Transferase Is Indispensable for Fungal Pathogenicity

In filamentous fungi, Sfp-type 4′-phosphopantetheinyl transferases (PPTases) activate enzymes involved in primary (α-aminoadipate reductase [AAR]) and secondary (polyketide synthases and nonribosomal peptide synthetases) metabolism. We cloned the PPTase gene PPT1 of the maize anthracnose fungus Colletotrichum graminicola and generated PPTase-deficient mutants (Δppt1). Δppt1 strains were auxotrophic for Lys, unable to synthesize siderophores, hypersensitive to reactive oxygen species, and unable to synthesize polyketides (PKs). A differential analysis of secondary metabolites produced by wild-type and Δppt1 strains led to the identification of six novel PKs. Infection-related morphogenesis was affected in Δppt1 strains. Rarely formed appressoria of Δppt1 strains were nonmelanized and ruptured on intact plant. The hyphae of Δppt1 strains colonized wounded maize (Zea mays) leaves but failed to generate necrotic anthracnose disease symptoms and were defective in asexual sporulation. To analyze the pleiotropic pathogenicity phenotype, we generated AAR-deficient mutants (Δaar1) and employed a melanin-deficient mutant (M1.502). Results indicated that PPT1 activates enzymes required at defined stages of infection. Melanization is required for cell wall rigidity and appressorium function, and Lys supplied by the AAR1 pathway is essential for necrotrophic development. As PPTase-deficient mutants of Magnaporthe oryzea were also nonpathogenic, we conclude that PPTases represent a novel fungal pathogenicity factor.

Marine Indole Alkaloids

Marine indole alkaloids comprise a large and steadily growing group of secondary metabolites. Their diverse biological activities make many compounds of this class attractive starting points for pharmaceutical development. Several marine-derived indoles were found to possess cytotoxic, antineoplastic, antibacterial and antimicrobial activities, in addition to the action on human enzymes and receptors. The newly isolated indole alkaloids of marine origin since the last comprehensive review in 2003 are reported, and biological aspects will be discussed.

Radical Addition to Iminium Ions and Cationic Heterocycles

Carbon-centered radicals represent highly useful reactive intermediates in organic synthesis. Their nucleophilic character is reflected by fast additions to electron deficient C=X double bonds as present in iminium ions or cationic heterocycles. This review covers diverse reactions of preformed or in situ-generated cationic substrates with various types of C-radicals, including alkyl, alkoxyalkyl, trifluoromethyl, aryl, acyl, carbamoyl, and alkoxycarbonyl species. Despite its high reactivity, the strong interaction of the radical’s SOMO with the LUMO of the cation frequently results in a high regioselectivity. Intra- and intermolecular processes such as the Minisci reaction, the Porta reaction, and the Knabe rearrangement will be discussed along with transition metal and photoredox catalysis or electrochemical methods to generate the odd-electron species.

Carbohydrate nanocarriers in biomedical applications: functionalization and construction

The specific targeting of either tumor cells or immune cells in vivo by carefully designed and appropriately surface-functionalized nanocarriers may become an effective therapeutic treatment for a variety of diseases. Carbohydrates, which are prominent biomolecules, have shown their outstanding ability in balancing the biocompatibility, stability, biodegradability, and functionality of nanocarriers. The recent applications of sugar (mono/oligosaccharides and/or polysaccharides) for the development of nanomedicines are summarized in this review, including the application of carbohydrates for the surface-functionalization of various nanocarriers and for the construction of the nanocarrier itself. Current problems and challenges are also addressed.

Gems from traditional north-African medicine: medicinal and aromatic plants from Sudan.

Sudanese folk medicine represents a unique blend of indigenous cultures with Islamic, Arabic and African traditions. In addition, Sudan encompasses different terrains and climatic zones, ranging from desert and semi-desert in the north to equatorial with a short rainy season (semi-aridand semi-humid) in the centre to equatorial with a long rainy season (arid-humid and equatorialhumid) in the south. This variation contributes to the immense diversity of vegetation in the region. The flora of Sudan consists of 3137 species of flowering plants belonging to 170 families and 1280 genera. It is estimated that 15% of these plants are endemic to Sudan. The intersection of diverse cultures and the unique geography holds great potential for Sudanese herbal medicine. Medicinal and aromatic plants and their derivatives represent an integral part of life in Sudan. Indigenous remedies are the only form of therapy available to the majority of poor people. It has been estimated that only 11% of the population has access to formal health care. Therefore, research on the desired pharmacological effects and possible unwanted side effects or toxicity is required to improve efficacy and safety of Sudanese herbal medicine. In the future, it would be preferable to promote the use of traditional herbal remedies by conversion of raw plant material into more sophisticated products instead of completely replacing the traditional remedies with synthetic products from industrialized countries. The present review gives an overview of traditional Sudanese medicinal and aromatic herbs and their habitats, traditional uses, and phytochemical constituents.

Cyclocondensation of α-Aminonitriles and Enones: A Short Access to 3,4-Dihydro-2H-pyrrole 2-carbonitriles and 2,3,5-Trisubstituted Pyrroles

The reaction of alpha,beta-unsaturated carbonyl compounds with aminoacetonitrile hydrochloride furnishes 3,5-disubstituted 3,4-dihydro-2H-pyrrole-2-carbonitriles in a one-pot reaction sequence. While these products can serve as starting materials for the preparation of polysubstituted pyrrolizidines, they are kinetically stable against the base-induced elimination of HCN. In contrast, their 2-substituted analogues obtained from alpha-substituted alpha-aminonitriles can be readily converted to the corresponding 2,3,5-trisubstituted pyrroles under microwave irradiation. The key step presumably involves the thermal electrocyclization of a stabilized 2-azapentadienyl anion formed by condensation of the reactants and subsequent deprotonation.

Combinatorial solid-phase synthesis using D-galactose as a chiral five-dimension-deversity scaffold

Abstract All five hydroxy groups of galactose as the scaffold are used for selective coupling of side chains in a combinatorial methodology by application of a set of orthogonally stable protecting groups in combination with a thioglycoside anchor.