Versatile Multicomponent Reaction Macrocycle Synthesis Using α-Isocyano-ω-carboxylic Acids

Abstract

The direct macrocycle synthesis of α-isocyano-ω-carboxylic acids via an Ugi multicomponent reaction is introduced. This multicomponent reaction (MCR) protocol differs by being especially short, convergent, and versatile, giving access to 12-22 membered rings.

Two‐Step Synthesis of Complex Artificial Macrocyclic Compounds

“…The linker moiety is decorated with orthogonal α,ω‐functional groups that can be macrocyclized by another diverse chemistry. Recently, we published an example of this general concept, where we synthesized the linker motif by employing Ugi tetrazole chemistry, followed by a macrocyclization using a second Passerini or Ugi multicomponent reaction (MCR) . Herein, we wanted to create a manifold of artificial macrocycles through an even shorter sequence involving an initial linear diversification, followed by an exponential diversification step of macrocyclization using Ugi MCR, thereby resulting in an overall 2‐step synthesis of complex macrocycles (Figure and Scheme ).…”

Traceless Solid‐Phase Synthesis of Fused Chiral Macrocycles via Conformational Constraint‐Assisted Cyclic Iminium Formation

“…[18] Carbon bond saturation (sp 3 carbons) and the presence of chirality are the critical features that were typically underrepresented in early screening libraries but are frequently presentinnatural (and bioactive) products. [20] The recent reports describing multicomponent reaction [21] and successive ring expansion [22,23] testify to the current interest in the development of synthetic methods for macrocyclization. [19] Complexm olecular scaffolds are key structural components of av ast number of natural products with diverse biological activities.…”

“…Numerous methods have been devised and used to close the ring from acyclic intermediates, including macrolactamization and macrolactonization, substitution chemistry, ring‐closing metathesis, the Wittig reaction, organometallic methods, cycloaddition, multicomponent reactions, and ring expansion, as detailed in an excellent recent review by Peterson . The recent reports describing multicomponent reaction and successive ring expansion testify to the current interest in the development of synthetic methods for macrocyclization. However, a general methodology to access fused and bridged large rings in one step is not available, although it would be highly desirable.…”

Two‐Step Synthesis of Complex Artificial Macrocyclic Compounds

“…We envisioned alinker moiety that makes use of simple and versatile chemistry.T he linker moiety is decorated with orthogonal a,w-functional groups that can be macrocyclized by another diverse chemistry.R ecently,w ep ublished an example of this general concept, where we synthesized the linker motif by employing Ugi tetrazole chemistry,followed by amacrocyclization using as econd Passerini or Ugi multicomponent reaction (MCR). [14,15] Herein, we wanted to create am anifold of artificial macrocycles through an even shorter sequence involving an initial linear diversification, followed by an exponential diversification step of macrocyclization using Ugi MCR, thereby resulting in an overall 2-step synthesis of complex macrocycles (Figure 1a nd Scheme 1).…”