Transcyclic C–H functionalization of cyclic saturated fatty acids

On May 31, 2023, Beijing time, the team of Yu Jinquan of Scripps Research Institute in the United States published a research result entitled “Transannular C–H Functionalization of Cycloalkane Carboxylic Acids” in the journal Nature.

In this study, a series of cyclic saturated fatty acids were cross-arylation of cyclic saturated fatty acids through novel ligand design, and the skeleton structures with diverse functions were synthesized with high regional selectivity and stereoselectivity.

The corresponding author of the paper is Yu Jinquan; The first authors are Kang Guowei, Daniel A. Strassfeld, and Sheng Tao.

Cyclic organic molecules are commonly found in natural products and drug molecules. In fact, most small molecule drugs contain at least one ring system because of the loop’s ability to control the shape of the molecule and increase the oral utilization rate of the drug. Therefore, it is extremely necessary to synthesize functionalized carbon rings directly and stereoselectively. Organic chemists often use cycloaddition or intramolecular cyclization reactions of chain compounds to construct cyclic systems. However, those strand-like precursors often require multi-step reactions, and cyclization can be challenging in itself.

Figure 1: Biologically active γ-aryl carbon ring compounds.

Complex carbon ring compounds can be achieved by modifying existing cyclic compounds, such as cyclic alkyl ketones or terpene chiral compounds. But traditional methods to transform the functional groups in these compounds into the desired structure often requires tedious steps. C-H activation offers a new strategy to avoid this limitation and quickly and efficiently synthesize a series of functionalized cyclic skeletons. However, the implementation of this strategy depends on the breakthrough development of C-H bond region selectivity methods. C-H bonds adjacent to the guide group are more active than C-H bonds farther from the guide group. Therefore, in the presence of competing neighboring C-H bonds, it is still a great challenge to achieve selective functionalization of remote C-H bonds. This is especially true for cyclic systems, as activation of remote C-H bonds requires breaking of transcyclic C-H bonds to form tense, bridged ring annular palladium.

Figure 2: A, Molecular editing strategies for traditional cyclic compounds. B, C-H bond-activated transcyclic reaction strategy.

Recently, the guide group strategy based on macrocyclic transition states has solved the control problem of remote C(sp2)-H activation of aromatic compounds. However, reports of C-H functionalization of saturated naphthenes are mostly limited to neighboring locations. Transcyclic C-H activation has also been reported, but the vast majority are performed by five-membered cyclic palladium chelates. Nitrogen atoms are required on or directly connected to the ring for remote C-H bond activation (Figure 2). Functionalization by six-membered cyclic palladium chelate would be a more general and general solution, but only a few reports have been obtained, either with general regional selectivity or the need for special bicyclic substrates. And due to the challenging nature of methylene C-H activation, almost all reports of cross-loop functionalization use substrates with pre-installed double-tooth guide groups. This greatly limits the range of applications of these reactions and the possible derivation of the products. Therefore, there is an urgent need to develop a general method to realize the primitive functional group-oriented transloop functionalization of simple monocyclic substrates.

The team of Jinquan Yu of the Scripps Institute has preliminarily realized the molecular editing of the saturated cyclic fatty acid backbone, that is, the transcyclic γ-selective arylation of a series of small ring to medium ring aliphatic carboxylic acids. The quininecyclo-pyridone ligand promotes transcyclic γ-arylation of pentato to octamembered cyclocarboxylic acids. (Figure 3)

Figure 3: Representative substrate range (pentamembered to octamembered cyclocarboxylic acid).

Transcyclic arylation of quaternary rings is achieved by dual C-H bond activation of carboxylic acids and aromatic hydrocarbons. (Figure 4)

Figure 4: Transcyclic arylation of cyclobutanecarboxylic acid.

This method is well compatible with more active β-C-H bonds, and selectively achieves cross-cyclic arylation at the γ-position in high regions, synthesizing a range of valuable compounds that previously required up to 10 steps. It is worth noting that cyclic fatty acids and their derivatives have important biological activity, making their value in medicinal chemistry particularly important. This approach will simplify the synthesis of γ-arylated cyclic alkanes and facilitate the design and development of novel drugs. (Source: Science Network)

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