Expansion of macrolide chemical space: synthesis of a library of THF containing macrolides and total synthesis of marine macrolides salarins A and C

In the seven decades since their discovery, macrolide natural products have led to some of the most revolutionary medicines of the 20th and 21st centuries. Owing to these successes, macrolides continue to be the subject of research efforts with an emphasis placed on accessing synthetic and naturally occurring macrolides with demonstrable biological activity. Toward contributing to these endeavors, and expanding the chemical space occupied by bioactive macrolides, we describe two complementary platforms that provide access to both synthetic and natural bioactive macrolides. In the first of these platforms, we describe the use of a model to select candidate macrolides for synthesis based on their molecular similarity to a small family of naturally occurring bioactive macrolides. Access to these de novo macrolides is achieved through: (i) proline catalyzed α-chloroaldol reaction to create most chiral coupling partners; (ii) union of the chiral coupling partners through Horner-Wadsworth-Emmons olefination or esterification; (iii) ring-closing metathesis to close the macrocycle; and (iv) a late-stage Nozaki-Hiyama-Kishi coupling to add diversity to the macrolides. Through this strategy a library (>150 members) of novel THF containing macrolides were prepared and evaluated in a cross section of bioassays, and several library members were found to have moderate activity against either prokaryotic or eukaryotic cells. In the second platform, total synthesis of the scarce anticancer marine macrolide salarin C is achieved and features: (i) proline catalyzed α-chloroaldol reaction to prepare the key chiral phosphonate coupling partner; (ii) Ru-mediated ring-closing metathesis to form the macrocycle; (iii) macrocyclic substrate-controlled epoxidation of the C12-C13 allylic alcohol to form the threo epoxy alcohol; and (iv) Julia-Kocienski olefination to install the side chain. Moreover, the biomimetic oxidation-Wasserman rearrangement of salarin C to salarin A is achieved. Through minor modification of this platform work toward the biomimetic synthesis of a collection of salarin analogues is presented and culminates in the total synthesis of salarin F confirming the presence of a C17-(R)-configured chloride. Finally, a strategy for adapting this platform to the preparation of synthetic salarin congeners is discussed.