I. Total Synthesis of Microcin SF608 and (±)-Gelsemoxonine II. Novel Reagents for Amine Selective Bioconjugation

Microcin SF608 (I) is a member of the aeruginosin serine protease inhibitors (Figure 1). This novel class of cyanobacterial non-ribosomal peptides exhibits a strong inhibitory activity against pharmaceutically relevant serine proteases such as thrombin or trypsin. The aeruginosins share a common 2-carboxy-6-hydroxyoctahydroindole (Choi) core fragment. We present a synthetic strategy towards microcin SF608. The Choi core of the natural product has been prepared using the intramolecular nucelophilic opening of oxabicyclo[2.2.1]heptane II promoted by the Lewis acid TMSOTf (Figure 1, box). The resulting product III could be readily converted into microcin SF608. Moreover, the reported synthesis features an unusual regioselective epoxide reduction mediated by Cp2TiCl. Detailed mechanistic investigations have led to the hypothesis that an intramolecular hydrogen atom delivery is responsible for the regioselectivity observed. Furthermore, this transformation was found to be of general use for the directed reductive opening of various epoxide substrates. Figure 1. Aeruginsosin serine protease inhibitor microcin SF608 and key step towards its total synthesis. Alkaloids isolated from the plant genus Gelsemium have been intriguing targets for synthetic chemists over more than 30 years due to their highly complex and compact structures. Only recently, gelsemoxonine (IV) has been isolated as a novel member of this natural product class (Figure 2). Its structure incorporates an unusual azetidine ring embedded in a compact polycyclic framework. Furthermore, a spiro-fused oxindole ring forms part of a series of six contiguous stereocenters arranged around the gelsemoxonine core. We herein document the total synthesis of this structurally intriguing gelsemium alkaloid. We have employed the acid mediated ring contraction of a spirocyclopropane isoxazolidine V to provide a highly substituted β-lactam product VI as a key transformation (Figure 2, box). The oxindole ring is constructed through a highly diastereoselecive xiii reductive Heck reaction. Final introduction of the ethyl ketone functionality was achieved using a directed hydrosilylation protocol. Experimental studies on the key ring contraction have prompted us to propose a novel mechanistic scheme for this unprecedented transformation. Figure 2. Gelsemoxoinine and key step towards its total synthesis. Bioconjugative chemistry has emerged as a powerful tool for the modification of various classes of biomolecules. The coupling of two biochemical entities enables the construction of compounds exhibiting novel functional properties. This concept can be employed to study and characterize the function and behavior of biomolecules. We herein report a novel bioconjugative technique relying on the coupling reaction of aryl diazonium salt VII with amino groups on proteins and peptides furnishing amide products VIII (Figure 3). Notably, tyrosine residues and other electron rich aromatic rings, which have been previously reported to react with diazonium salts, are compatible with the system developed. The new technique allows for the direct coupling of numerous highly functionalized natural products to protein substrates. Figure 3. Bioconjugative coupling of diazonium salts and proteins.