Biomimetic synthesis and structural refinement of the macrocyclic dimer aminoglycoside 66-40C—the remarkably selective self-condensation of a putative aldehyde intermediate in the submerged culture medium producing sisomicin

Abstract

Aminoglycoside 66-40C, an unprecedented 16-membered bis-azadiene macrocyclic natural product isolated from the Micromonospora producer of the antibiotic sisomicin, was synthesized following a biomimetic strategy which definitively established its origin as arising from a remarkably selective non-enzymatic macro-dimerization.

Structural and kinetic study of self-assembling macrocyclic dimer natural product aminoglycoside66-40C and unnatural variants

“…We have previously reported the validation of our hypothesis through the concise biomimetic synthesis of aminoglycoside 66-40C (3), and demonstrated its quantitative self-condensation from aldehyde 2 in aqueous solution. 8 Furthermore, using heteronuclear correlation spectroscopic analysis of the macrocyclic core we confirmed the imine location on N-3 of the 2-deoxystreptamine ring B as originally presumed. 8 Moreover, nuclear Overhauser effects (nOe) observed across neighbors of the 6 0 -imine proton led us to propose a refined s-trans conformation for the macrocycle bis-azadiene bridges (Fig.…”

“…8 Furthermore, using heteronuclear correlation spectroscopic analysis of the macrocyclic core we confirmed the imine location on N-3 of the 2-deoxystreptamine ring B as originally presumed. 8 Moreover, nuclear Overhauser effects (nOe) observed across neighbors of the 6 0 -imine proton led us to propose a refined s-trans conformation for the macrocycle bis-azadiene bridges (Fig. 1).…”

“…6,7 The intriguing biosynthetic origin of aminoglycoside 66-40C remained unchallenged for over four decades, and likewise, its potential biological roles are subject to speculation. In our preliminary studies on the synthesis of aminoglycoside 66-40C, 8 we hypothesised that it may arise as the product of a non-enzymatic self-condensation of a putative monomeric 6 0 -aldehydo sisomicin (2), itself potentially produced via transamination or oxidation of the 6 0 -allylic amino group in sisomicin. 8 The plausible biosynthetic origin and speculative biological roles of aminoglycoside 66-40C are illustrated in Fig.…”

Comprehensive review of chemical strategies for the preparation of new aminoglycosides and their biological activities

“…Another useful approach to produce AG homodimers involves imine intermediates. 204 An example of such reaction is that of the preparation of a SIS homodimer in 7 steps (Fig. 56A).…”

Application of One-Pot Three-Component Condensation Reaction for the Synthesis of New Organophosphorus–Sulfur Macrocycles

“…21 The mechanism for the formation of compounds 1-3 and 5-12 might be similar to that previously reported. 6 The four-membered-ring thionation reagent might be in equilibrium with the monomeric species A (Scheme 1), which is believed to be the true reactive species in solution. 22,23 Two possible reaction paths (I and II) involving ring expansion reactions to give macrocycles 1-3 and 5-12 are then possible.…”