Multidrug-resistant, gram-negative bacterial organisms are quickly becoming either effectively untreatable or only treatable with toxic antimicrobials. As a result, the CDC has now categorized several gram-negative bacteria to their top pathogen threat level. Streptothricin F is an antibiotic that was discovered over 70 years ago. It has an impressive activity spectrum against otherwise resistant Gram-negative pathogens. However, initial concerns around toxicities and the availability of alternative antibiotics precluded its development, and it has largely been forgotten. We hypothesize that based on the availability of modern synthetic approaches that the streptothricin scaffold can be modified to optimize its properties and develop a much needed therapeutic with activity against Gram-negative organisms. Only one single synthetic route for the preparation of streptothricin F has been published thus far. We developed a shorter, convergent, highly tractable synthetic approach (for streptothricin F, the projected longest linear reaction sequence is 17 steps and the number of total reaction steps is reduced by 22% over the original total synthesis) enabling the preparation of streptothricin F and analogues thereof. Our goal to is develop a convergent synthesis for streptothricin F that allows extensive SAR exploration of the three primary molecular constituents of this molecule. We propose to make streptothricin F and a manageable number of analogues designed to probe the significance of the streptolidine lactam moiety, the D-gulosamine core, and the β-lysine homopolymer. Therefore, we designed a convergent synthetic route (Fig. 1), by which gulosamine precursor 1 is first modified by streptolidine lactam and then by β-lysine (Route A) or first by β-lysine and then by streptolidine lactam (Route B). The presentation will outline studies towards the total synthesis of streptothricin F and its coupling partners, including a novel approach to streptolidine lactam.

Total synthesis of streptothricin F and streptolidine lactam

2019 Fall National Meeting

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