INAUGURAL ARTICLE by a Recently Elected Academy Member:Chirality-matched catalyst-controlled macrocyclization reactions

Macrocycles, formally defined as compounds that contain a ring with 12 or more atoms, continue to attract great interest due to their important applications in physical, pharmacological, and environmental sciences. In syntheses of macrocyclic compounds, promoting intramolecular over intermolecular reactions in the ring-closing step is often a key challenge. Furthermore, syntheses of macrocycles with stereogenic elements confer an additional challenge, while access to such macrocycles are of great interest. Herein, we report the remarkable effect peptide-based catalysts can have in promoting efficient macrocyclization reactions. We show that the chirality of the catalyst is essential for promoting favorable, matched transition-state relationships that favor macrocyclization of substrates with preexisting stereogenic elements; curiously, the chirality of the catalyst is essential for successful reactions, even though no new static (i.e., not “dynamic”) stereogenic elements are created. Control experiments involving either achiral variants of the catalyst or the enantiomeric form of the catalyst fail to deliver the macrocycles in significant quantity in head-to-head comparisons. The generality of the phenomenon, demonstrated here with a number of substrates, stimulates analogies to enzymatic catalysts that produce naturally occurring macrocycles, presumably through related, catalyst-defined peripheral interactions with their acyclic substrates.

Macrocyclic compounds are known to perform a myriad of functions in the physical and biological sciences. From cyclodextrins that mediate analyte separations (1) to porphyrin cofactors that sit in enzyme active sites (2, 3) and to potent biologically active, macrocyclic natural products (4) and synthetic variants (5–7), these structures underpin a wide variety of molecular functions (Fig. 1A). In drug development, such compounds are highly coveted, as their conformationally restricted structures can lead to higher affinity for the desired target and often confer additional metabolic stability (8–13). Accordingly, there exists an entire synthetic chemistry enterprise focused on efficient formation and functionalization of macrocycles (14–18).Open in a separate windowFig. 1.(A) Examples of macrocyclic compounds with important applications. HCV, hepatitis C virus. (B) Use of chiral ligands in metal-catalyzed or mediated stereoselective macrocyclization reactions. (C) Remote desymmetrization using guanidinylated ligands via Ullmann coupling. (D) This work: use of copper/peptidyl complexes for macrocyclization and the exploration of matched and mismatched effect.In syntheses of macrocyclic compounds, the ring-closing step is often considered the most challenging step, as competing di- and oligomerization pathways must be overcome to favor the intramolecular reaction (14). High-dilution conditions are commonly employed to favor macrocyclization of linear precursors (19). Substrate preorganization can also play a key role in overcoming otherwise high entropic barriers associated with multiple conformational states that are not suited for ring formation. Such preorganization is most often achieved in synthetic chemistry through substrate design (14, 20–22). Catalyst or reagent controls that impose conformational benefits that favor ring formation are less well known. Yet, critical precedents include templating through metal-substrate complexation (23, 24), catalysis by foldamers (25) or enzymes (26–29), or, in rare instances, by small molecules (discussed below). Characterization of biosynthetic macrocyclization also points to related mechanistic issues and attributes for efficient macrocyclizations (30–34). Coupling macrocyclization reactions to the creation of stereogenic elements is also rare (35). Metal-mediated reactions have been applied toward stereoselective macrocyclizations wherein chiral ligands transmit stereochemical information to the products (Fig. 1B). For example, atroposelective ring closure via Heck coupling has been applied in the asymmetric total synthesis of isoplagiochin D by Speicher and coworkers (36–40). Similarly, atroposelective syntheses of (+)-galeon and other diarylether heptanoid natural products were achieved via Ullman coupling using N-methyl proline by Salih and Beaudry (41). Finally, Reddy and Corey reported the enantioselective syntheses of cyclic terpenes by In-catalyzed allylation utilizing a chiral prolinol-based ligand (42). While these examples collectively illustrate the utility of chiral ligands in stereoselective macrocyclizations, such examples remain limited.We envisioned a different role for chiral catalysts when addressing intrinsically disfavored macrocyclization reactions. When unfavorable macrocyclization reactions are confronted, we hypothesized that a catalyst–substrate interaction might provide transient conformational restriction that could promote macrocyclization. To address this question, we chose to explore whether or not a chiral catalyst-controlled macrocyclization might be possible with peptidyl copper complexes. In the context of the medicinally ubiquitous diarylmethane scaffold, we had previously demonstrated the capacity for remote asymmetric induction in a series of bimolecular desymmetrizations using bifunctional, tetramethylguanidinylated peptide ligands. For example, we showed that peptidyl copper complexes were able to differentiate between the two aryl bromides during C–C, C–O, and C–N cross-coupling reactions (Fig. 1C) (43–45). Moreover, in these intermolecular desymmetrizations, a correlation between enantioselectivity and conversion was observed, revealing the catalyst’s ability to perform not only enantiotopic group discrimination but also kinetic resolution on the monocoupled product as the reaction proceeds (44). This latter observation stimulated our speculation that if an internal nucleophile were present to undergo intramolecular cross-coupling to form a macrocycle, stereochemically sensitive interactions (so-called matched and mismatched effects) (46) could be observed (Fig. 1D). Ideally, we anticipated that transition state–stabilizing interactions might even prove decisive in matched cases, and the absence of catalyst–substrate stabilizing interactions might account for the absence of macrocyclization for these otherwise intrinsically unfavorable reactions. Herein, we disclose the explicit observation of these effects in chiral catalyst-controlled macrocyclization reactions.