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

Abstract

Following 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.