The evolution of bacteria with resistance towards clinically used antibiotics requires constant efforts in the search for new antibacterial compounds to target these menacing strains. [1] Recent advances in screening technologies allowed a team of scientists at Merck to develop and employ a target-based, whole-cell, high-throughput screening assay for the detection of inhibitors of the condensing enzymes FabH and FabF in the biosynthesis of fatty acids in bacteria. [2, 3] Their efforts were rewarded with the discovery of the much hailed antibiotics platensimycin (1) [2] and platencin (2, Scheme 1). [3] Isolated from a new strain of Streptomyces platensis MA7339 found in a soil sample collected in Spain, platencin ( 2) is a potent inhibitor of Staphylococcus aureus fatty acid biosynthesis (IC 50 = 0.45 mm), SaFabH (IC 50 = 9.2 mm), and SaFabF (IC 50 = 4.6 mm). Platencin (2) exhibits broad-spectrum antibacterial activity against many Gram-positive pathogens that show resistance to current antibiotics (MIC 50 0.06-4 mg mL À1 ), including S. aureus, methycillin-resistant S. aureus (MRSA), macrolide-resistant MRSA, linezolid-resistant MRSA, vancomycin intermediate S. aureus, vancomycin-resistant enterococci, and Streptomyces pneumoniae. [3] Impressively, this new antibiotic demonstrated a thousandfold reduction of S. aureus colony-forming units in an in vivo mouse model compared to an untreated control. [3] Whereas several syntheses of platensimycin (1) and its analogues have been reported, [4] none for platencin ( 2) has yet appeared in the literature. Herein we report an enantioselective total synthesis of this newly discovered and highly promising antibiotic.
The molecular structure of platencin (2) resembles that of platensimycin (1) in that they both contain an identical domain (comprising C 1 -C 9 , C 17 , C 1' -C 8' -N 8' ) but they differ significantly in their C 8 -C 16 core domains (Scheme 1). As such, a distinctly different approach from those employed to synthesize platensimycin ( 1) is required to construct the "right-hand" core structure of the molecule (enone 3), while the rest of the pathway to platencin (2) should, in principle, follow that already charted for platensimycin (1). [4a] Scheme 2 outlines, in retrosynthetic format, the devised strategy for the synthesis of platencin (2), which defines enone 3 as the key precursor to the target molecule and requires amide coupling Scheme 2. Retrosynthetic analysis of platencin (2). TMSE = 2-(trimethylsilyl)ethyl, SEM = 2-(trimethylsilyl)ethoxymethyl, TIPS = triisopropylsilyl. Scheme 1. Structures of platensimycin (1) and platencin (2).