Total Synthesis and Antibiotic Properties of Amino‐Functionalized Aromatic Terpenoids Related to Erogorgiaene and the Pseudopterosins

Abstract

AbstractFollowing a concept recently introduced by Hergenrother,[6] the present study addresses the question of whether certain antimicrobially active aromatic (marine) natural products can be converted into more potent broad‐spectrum antibiotics by introducing an aminoalkyl side chain. To this end, phenolic mono‐ and sesquiterpenoids (incl. carvacrol, xanthorrhizol, and 7‐hydroxycalamene) as well as the diterpenes 7‐hydroxyerogorgiaene and 9‐deoxypseudopterosin A were converted into amino‐functionalized analogs that display either an amino‐methyl or a 2‐amino‐ethoxy substituent in place of (or next to) the OH group. This was achieved either by Pd‐catalyzed nitromethylation/reduction of the aryltriflates, by O‐alkylation of the phenols with bromoacetonitrile and subsequent reduction, or by ortho‐hydroxymethylation/amination. During the study, an efficient enantioselective total synthesis of 7‐hydroxyerogorgiaene (8 steps, 29 % overall yield) and 9‐deoxypseudopterosin A (9 steps, 30 % overall yield) was elaborated using an asymmetric cobalt‐catalyzed hydrovinylation (91 % ee) of 3‐methoxy‐4‐methyl‐styrene as the chirogenic step. Other important C−C bond forming steps include a Pd‐catalyzed Suzuki cross‐coupling and diastereoselective Lewis acid‐mediated cyclization reactions. A total of 16 amino derivatives of natural products were prepared and subsequently tested for their antibacterial properties. Some of the diterpene‐derived amines showed high efficacy, not only against Gram‐positive (S. aureus SG511, S. aureus HG003, B. subtilis 168; MIC=0.5 to 2 μg/ml), but also against Gram‐negative bacterial strains (E. coli K12; E. coli I‐11276b; MIC=8 to 32 μg/ml). This clearly supported the underlying working hypothesis.