9‐Membered Carbocycles: Strategies and Tactics for their Synthesis

Abstract

Many natural products comprising a nine-membered carbocyclic core structure exhibit interesting biological effects. However, only a minority have succumbed to their synthesis in the past. The synthesis of functionalized nine-membered carbocycles still remains a challenging goal for synthetic chemists, mainly due to their high ring strain. Different strategies to overcome the unfavorable enthalpic and entropic factors associated with their formation are highlighted in this Concept article. The presented methods are classified into two different categories: (1) the ring-expansion of smaller rings or the ring-contraction of larger rings and (2) the direct cyclization of acyclic precursors.

Evolution of a Strategy for the Total Synthesis of (+)‐Cornexistin

“…Contrary to those cyclic components, we opted for the intermolecular merging ( III ) of a Z ‐vinyl iodide and an aldehyde via 1,2‐addition chemistry. One of the major challenges for the synthesis of 1 is the construction of the medium‐sized nine‐membered carbocycle (Figure 2b) [8] . The Clark group was able to overcome the enthalpic and entropic factors by initially dissecting the nine‐membered ring between C1 and C2.…”

“…One of the major challenges for the synthesis of 1 is the construction of the medium‐sized nine‐membered carbocycle (Figure 2 b). [8] The Clark group was able to overcome the enthalpic and entropic factors by initially dissecting the nine‐membered ring between C1 and C2. By employing a ring‐closing metathesis (RCM) reaction the cyclized product was delivered in good yields.…”

Divergent Strategy for Diastereocontrolled Synthesis of Small- and Medium-Ring Architectures

“…They can selectively target protein surfaces not easily accessed by conventional small molecules (Figure ). These rings remain a challenge for synthetic chemists, principally from unfavorable enthalpy, entropy, and transannular interactions …”

“…The scarcity of 8- to 12-membered rings among clinically approved drugs reflects these difficulties. ,− Recent exploration of drug candidates containing medium-ring nitrogen-based heterocycles highlighted the importance of the conformational constraints inherent in these structures. ,− Today, it is widely acknowledged that the use of medium-sized rings in phenotypic screens is a powerful tool for the discovery of first-in-class drug candidate leads. This property is due to the conformational constraints and the sp 3 content inherent in these systems .…”

Thioether-Directed C4-Selective C–H Acylmethylation of Indoles Using α-Carbonyl Sulfoxonium Ylides

“…Among the series of medium-sized cyclic architectures, nine-membered systems are still one of the most difficult rings to access because of the significant entropic and enthalpic penalties. , Accordingly, we tackled this issue relying on the intramolecular hydroarylation under gold catalysis (Scheme ). Reduction of the carbonyl moiety within 3aa-1 by LiAlH 4 furnished the alcohol 3aa-6 , which was further transformed to the corresponding propargyl ether 3aa-7 upon treatment with propargyl bromide.…”