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

Abstract

Natural products comprising chiral molecular scaffolds containing fused medium-sized cycles and macrocycles represent an important and relevant pharmacological target for the discovery and development of new drugs. Here, we describe traceless solid-phase synthesis of acyclic intermediates amenable to cyclization to medium (11) and large (12) fused rings. The key aspect of the synthetic strategy is incorporation of a specific conformation constraint that facilitates cyclization in favor of 11- and 12-membered rings rather than possible 7-membered ones. The role of constraints in preorganization required for cyclization is supported by computational analysis. The synthesis involves cyclic N-sulfonyliminium-nucleophilic addition chemistry as the key ring-forming reaction and proceeds with complete stereocontrol of the newly formed stereogenic center. We document the scope and limitations of this strategy in the synthesis of 11+5, 11+6, 11+7, and 12+6 fused rings representing molecular scaffolds with 3D architecture that mimic complex natural products.

Solid‐Phase Synthesis of Tetramic Acid via Resin‐Bound Enol Ethers as a Privileged Scaffold in Drug Discovery

“…We developed a practical route for the synthesis of diverse derivatives of tetramic acid, a natural product with a broad range of pharmacologically relevant activities. We exploited the advantages of SP synthesis and designed the synthesis in a modular fashion using simple building blocks and user‐friendly reaction conditions following a strategy we frequently use for the synthesis of diverse heterocycles . To assess the feasibility of this synthetic route, we first prepared acyclic resin‐bound precursor 5 .…”

Traceless Solid-Phase Organic Synthesis

“…13 The last example involving the formation of iminium ions is the synthesis of fused chiral 11-and 12-membered rings. 367 Attempts to prepare a 12-membered ring under the described conditions were unsuccessful. To prove that hemiaminals were formed properly (in the case of derivatives that failed to obtain cyclized products), they were treated with MeOH to afford dimethyl acetals 1371.…”

“…Most of the contributions in this section come from Krchňák’s group. ,,− In studies on the synthesis of various fused heterocycles, such as [6,7,8 + 5,6,7] combinations of fused rings, attention has been paid to addressing the scope and limitations on the formation of different ring sizes …”

“…The last example involving the formation of iminium ions is the synthesis of fused chiral 11- and 12-membered rings . Two immobilization strategies were used.…”

Configuration-Dependent Medium-Sized Ring Formation: Chiral Molecular Framework with Three-Dimensional Architecture

“…Reducing the conformational space, enhancing the population of conformers prone to cyclization, has a positive effect on the cyclization outcome (see reviews in the literature , ). Indeed, we recently applied this strategy to the synthesis of 11-membered fused rings . In this report, we describe the insertion of a conformational constraint by incorporating a 2-aminocyclohexanecarboxylic acid instead of a β-Ala and successful cyclization to a seven-membered ring and, more interestingly, configuration-dependent eight-membered ring formation (structures in blue, Figure ).…”