An efficient protocol for direct catalytic alkynylation of ketoimines is described. The simultaneous activation of a soft Lewis basic terminal alkyne and a ketoimine bearing a thiophosphinoyl group by soft Lewis acid Cu(I) is crucial for high conversion. The reaction can be rendered asymmetric with a chiral bisphosphine ligand (S,S)-Ph-BPE.

The total synthesis of (+)-fawcettimine was completed in a highly stereoselective manner starting from the oxatricyclo[7.3.0.0(1,5)]dodecanedione derivative. The crucial step in this total synthesis involves the efficient construction of the azonane framework by the intramolecular Mitsunobu reaction. Furthermore, the first total synthesis of (+)-lycoposerramine-B was also accomplished via the common synthetic intermediate.

A direct catalytic asymmetric γ‐addition of allyl cyanide to aldehydes promoted by soft Lewis acid/hard Brønsted base cooperative catalysis is described. The resulting homoallylic alcohols bearing a Z‐configured α,β‐unsaturated nitrile allow rapid access to enantioenriched δ‐valerolactones.

The emergence of multidrug-resistant (MDR) Gram-negative bacteria has become a global problem. Among MDR Gram-negative bacteria, carbapenem-resistant Enterobacteriaceae (CRE), MDR Pseudomonas aeruginosa, and MDR Acinetobacter baumannii have limited treatment options and present serious threats. Therefore, strong countermeasures must be taken against these bacteria immediately. Accordingly, the focus of this review is on recent advances in the development of promising antibacterial agents against MDR Gram-negative bacteria. These agents include novel tetracyclines, polymyxins, β-lactams, β-lactam/βlactamase inhibitors, aminoglycosides, and peptide mimetics that have been recently approved or have shown promising results in clinical and preclinical development. This review summarizes these potent antibiotics in terms of their development status, mode of action, spectra of activity, and structure-activity relationship. Key words antibiotic; drug candidate; Gram-negative bacteria; carbapenem-resistant 2. Novel Tetracycline-class Antibiotics for MDR Gramnegative Bacteria Tetracycline antibiotics derived from natural products do not contain substituents at the C-7, C-8, and C-9 positions. However, the development of totally synthetic methods to synthesize tetracyclines has made it possible to modify these three positions, 21,22) providing novel and fully synthetic tetracyclines such as XERAVA and TP-6076, developed by Tetraphase Pharmaceuticals Inc. (Fig. 1). The introduction of an electron-withdrawing group at the C-7 position, and substitution at the C-9 position, significantly improved the antimicrobial activity of these synthetic tetracyclines. 23,24) XERAVA (eravacycline, TP-434) 25-27) was the first fully synthetic fluorocycline produced by Michael-Dieckmann reaction. 28) XERAVA was approved by the U.S. Food and Drug Administration (FDA) in August 27, 2018 for the treatment of

Novel aprosamine derivatives were synthesized for the development of aminoglycoside antibiotics active against multidrug-resistant Gram-negative bacteria. The synthesis of aprosamine derivatives involved glycosylation at the C-8′ position and subsequent modification (epimerization and deoxygenation at the C-5 position and 1-N-acylation) of the 2-deoxystreptamine moiety. All 8′-βglycosylated aprosamine derivatives (3a−h) showed excellent antibacterial activity against carbapenem-resistant Enterobacteriaceae and 16S ribosomal RNA methyltransferase-producing multidrug-resistant Gram-negative bacteria compared to the clinical drug, arbekacin. The antibacterial activity of 5-epi (6a−d) and 5deoxy derivatives (8a,b and 8h) of β-glycosylated aprosamine was further enhanced. On the other hand, the derivatives (10a,b and 10h) in which the amino group at the C-1 position was acylated with (S)-4-amino-2-hydroxybutyric acid showed excellent activity (MICs 0.25−0.5 μg/mL) against resistant bacteria that produce the aminoglycoside-modifying enzyme, aminoglycoside 3-N-acetyltransferase IV, which induces high resistance against parent apramycin (MIC > 64 μg/mL). In particular, 8b and 8h showed approximately 2-to 8-fold antibacterial activity against carbapenem-resistant Enterobacteriaceae and 8-to 16-fold antibacterial activity against resistant Grampositive bacteria, such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci, compared to apramycin. Our results showed that aprosamine derivatives have immense potential in the development of therapeutic agents for multidrugresistant bacteria.