Divergent Synthesis of Novel Cylindrocyclophanes that Inhibit Methicillin‐Resistant Staphylococcus aureus (MRSA)

Abstract

The cylindrocyclophanes are a family of macrocyclic natural products reported to exhibit antibacterial activity. Little is known about the structural basis of this activity due to the challenges associated with their synthesis or isolation. We hypothesised that structural modification of the cylindrocyclophane scaffold could streamline their synthesis without significant loss of activity. Herein, we report a divergent synthesis of the cylindrocyclophane core enabling access to symmetrical macrocycles by means of a catalytic, domino cross‐metathesis‐ring‐closing metathesis cascade, followed by late‐stage diversification. Phenotypic screening identified several novel inhibitors of methicillin‐resistant Staphylococcus aureus. The most potent inhibitor has a unique tetrabrominated [7,7]paracyclophane core with no known counterpart in nature. Together these illustrate the potential of divergent synthesis using catalysis and unbiased screening methods in modern antibacterial discovery.

Chemoenzymatic Synthesis of Cylindrocyclophanes A and F and Merocyclophanes A and D

“…The Hoye group and the Nicolaou group used Horner–Wadsworth–Emmons olefination and Ramberg–Bäcklund olefination to establish macrocyclic scaffolds, respectively [6] . Despite these advances, the chemical synthesis of other [7.7]paracyclophane natural products has not been reported, and structure–activity relationship (SAR) studies of these compounds are very limited [7] . Therefore, it is highly desirable to develop a concise and efficient synthetic route that can facilitate the structural diversification of [7.7]paracyclophane natural products and SAR studies.…”

“…To this end, our target molecules, including cylindrocyclophanes A and F and merocyclophanes A and D, are disconnected at C(7-8) and C(20-21) to afford monomeric compounds 5 a-d (Scheme 1). In contrast to the alkene metathesis and olefination approaches, the enzymatic Friedel-Crafts alkylation established the stereochemistry of C (7) and C(20) while forging the C(7-8) and C(20-21) connections. Previously, Balskus and co-workers demonstrated that CylK could catalyze the intermolecular Friedel-Crafts alkylation of several alkyl halides and resorcinols.…”

“…[6] Despite these advances, the chemical synthesis of other [7.7]paracyclophane natural products has not been reported, and structure-activity relationship (SAR) studies of these compounds are very limited. [7] Therefore, it is highly desirable to develop a concise and efficient synthetic route that can facilitate the structural diversification of [7.7]paracyclophane natural products and SAR studies. The biosynthetic route for cylindrocyclophanes was revealed with the identification of the cyl gene cluster from C. licheniforme ATCC 29412.…”

Ligand–Metal Cooperation Enables Net Ring-Opening C–C Activation/Difunctionalization of Cyclopropyl Ketones

“…The ring-opening C–C activation/cross-coupling of cyclopropyl ketones results in valuable γ-substituted silyl enol ethers − that can be challenging to access by other approaches (Scheme ). The most-developed approach to these products is conjugate addition under conditions to trap the enolate as the silyl enol ether, but this can be challenging for certain substitution patterns and functional groups.…”

Ligand-Metal Cooperation Enables Net C–C Activation Cross-Coupling Reactivity of Cyclopropyl Ketones

“…The ring-opening C-C activation/cross-coupling of cyclopropyl ketones results in valuable γ-substituted silyl enol ethers [29][30][31][32][33][34][35] that can be challenging to access by other approaches (Scheme 2). The mostdeveloped approach to these products is conjugate addition under conditions to trap the enolate as the silyl enol ether, but this can be challenging for certain substitution patterns and functional groups.…”