Total Synthesis of Hemerocallisamine I Paved by Gram-Scale Synthesis of (2S,4S)-4-Hydroxyglutamic Acid Lactone.

Total synthesis of the 2-formylpyrrole alkaloid hemerocallisamine I is presented, both in racemic and enantiopure form. Our synthetic strategy involves (2S,4S)-4-hydroxyglutamic acid lactone as the key intermediate. Starting from an achiral substrate, the target stereogenic centers were introduced by means of crystallization-induced diastereomer transformation (CIDT) in a highly stereoselective fashion. A Maillard-type condensation was crucial to constructing the desired pyrrolic scaffold.

Synthesis and structure-activity relationship of berkeleylactone A-derived antibiotics.

Berkeleylactone A is a potent 16-membered macrolactone antibiotic, recently isolated from a coculture of Berkeley Pit Lake fungi. Although its antimicrobial activity has already been investigated, little is known about the structure-activity relationship. Based on our previous synthetic studies, a series of berkeleylactone A derivatives were synthesized and evaluated for their in vitro antimicrobial activities against methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MRSA) strains. Our data confirmed the essential role of the embedded conjugated system and suggest a reversible sulfa-protection of the Michael acceptor as a viable option. Structurally simplified achiral macrolactam 8 showed the best inhibitory activity against S. aureus L12 (MRSA) with MIC50 values of 0.39 µg mL-1, 8-fold lower than those of berkeleylactone A. These studies may be of value in the development of more advanced candidates for antibiotic applications.

Total Synthesis of Berkeleylactone A.

The first total synthesis of the potent antibiotic berkeleylactone A is described in 10 steps with an overall yield of 9.5%. A key step of our concise route is a late-stage, highly diastereoselective, sulfa-Michael addition. The 16-membered macrocyclic lactone was formed via ring closing metathesis and subsequent chemoselective reduction. The absolute stereochemical configuration was confirmed by single-crystal X-ray analysis. Synthetic berkeleylactone A was tested against several methicillin-resistant Staphylococcus aureus strains, and its potent antibacterial activity was verified.

Stereoselective Synthesis of Functionalized α-Amino Acids Isolated by Filtration.

Crystallization-induced diastereomer transformation (CIDT) represents a highly appealing and convenient synthetic tool. Despite its numerous advantages, it remains rather rarely used due to its uncertain predictability to occur. Herein, we describe CIDT based on aza-Michael reactions of diversely functionalized ( E)-3-acylacrylic acids. This method provides direct access to a broad variety of α-amino acid derivatives in excellent stereochemical purities.

Synthesis and biological profiling of 6- or 7-(het)aryl-7-deazapurine 4'-C-methylribonucleosides.

The synthesis and biological activity profiling of a large series of diverse pyrrolo[2,3-d]pyrimidine 4'-C-methylribonucleosides bearing an (het)aryl group at position 4 or 5 is reported as well as the synthesis of several phosphoramidate prodrugs. These compounds are 4'-C-methyl derivatives of previously reported cytostatic hetaryl-7-deazapurine ribonucleosides. The synthesis is based on glycosylation of halogenated 7-deazapurine bases with 1,2-di-O-acetyl-3,5-di-O-benzyl-4-C-methyl-ß-d-ribofuranose followed by cross-coupling and nucleophilic substitution reactions. The final compounds showed low cytotoxicity and several derivatives exerted antiviral activity against HCV or Dengue viruses at micromolar concentrations.

Synthetic Chameleon Turns into Oximes, Nitrones, and Hydroxylamines when Exposed to Blue Light.

A metal-free, user-friendly photochemical transformation of nitroalkanes to oximes, nitrones, and hydroxylamines has been developed. The visible-light-induced reactions are catalyzed by the readily available photoredox organocatalyst 4CzIPN and use inexpensive amines as reductants. Broad in scope and tolerant of multiple functional groups and heterocycles, the transformation proceeds under mild conditions. Its synthetic potential was demonstrated in the formal total synthesis of amathaspiramide F. A basic insight into the reaction mechanism was gained with the help of an NMR study.

Synthesis, cytostatic, antimicrobial, and anti-HCV activity of 6-substituted 7-(het)aryl-7-deazapurine ribonucleosides.

A series of 80 7-(het)aryl- and 7-ethynyl-7-deazapurine ribonucleosides bearing a methoxy, methylsulfanyl, methylamino, dimethylamino, methyl, or oxo group at position 6, or 2,6-disubstituted derivatives bearing a methyl or amino group at position 2, were prepared, and the biological activity of the compounds was studied and compared with that of the parent 7-(het)aryl-7-deazaadenosine series. Several of the compounds, in particular 6-substituted 7-deazapurine derivatives bearing a furyl or ethynyl group at position 7, were significantly cytotoxic at low nanomolar concentrations whereas most were much less potent or inactive. Promising activity was observed with some compounds against Mycobacterium bovis and also against hepatitis C virus in a replicon assay.