Photoinduced Decatungstate-Catalyzed [3+2] Cycloaddition of Internal Alkynes Using Aliphatic Aldehydes as a Three-Carbon Synthon

In contrast to the prevalence of 1,3-dipolar cycloadditions, radical [3+2] annulations of alkynes are underexplored. Here, the authors describe [3+2] cycloadditions of various internal alkynes with readily accessible aliphatic aldehydes via photoinduced decatungstate catalysis.
Published in Chemistry

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Cyclopentanones are important structural motifs embedded in various natural products, pharmaceuticals, and bioactive compounds, such as PGE2, loxoprofen, and deconin B (Fig. 1). Meanwhile, they can serve as versatile intermediates in synthetic chemistry. Consequently, enormous efforts have been devoted to the construction of these scaffolds, including the ring expansion, carbene insertion, and intramolecular hydroacylation. However, the traditional methods rely on the use of prefunctionalized substrates that require multistep synthesis, thus calling for the development of more straightforward and robust protocols.

Figure 1. Selected bioactive molecules bearing cyclopentanones

Recently, by using SEt as a traceless directing group, we realized a photocatalytic sulfonylcarbocyclization of alkynes to synthesize cyclopentenes and indenes (Angew. Chem. Int. Ed. 2022, 61, e202110864) (Fig. 2a). We found that the sulfonyl group is pivotal for the anti-Baldwin 5-endo-trig radical cyclization through polar effects and spin delocalization. However, the more common non-terminal alkynes are not suitable for this carbocyclization reaction.

[3+2] Annulation is a powerful strategy for the fast assembly of five-membered rings. Specifically, the 1,3-dipolar cycloaddition of C-C double bonds has been widely developed for the synthesis of cyclopentanones. However, the radical [3+2] carbocyclization of alkynes, featuring the C-C bond formation on inert C-H bonds, is still a formidable challenge, due to the lack of suitable three-carbon (3C) building blocks and unfavorable 5-endo-trig closure. In light of recent developments on decatungstate-catalyzed C-H functionalization of aldehydes and our interest on 5-endo-trig radical cyclization, we envisioned that aliphatic aldehydes could be exploited as an ideal 3C component for the [3+2] carbocyclization of alkynes via hydrogen atom transfer (HAT)-induced double C-H functionalization (Fig. 2b). The polar effects and radical delocalization, both caused by the adjacent carbonyl group, may facilitate the 5-endo-trig radical closure.


Figure 2. Our previous work and proposal

In this work, after extensive trails, a photoinduced decatungstate-catalyzed [3+2] cycloaddition of various internal alkynes (Fig. 3), featuring the use of widely available alkyl aldehydes as a three-carbon synthon, is realized, which provides a direct and modular access to highly functionalized cyclopentanones that are difficult to obtain via traditional methods. Notable features of this process include the double C-H functionalization, mild and redox-neutral conditions, 100% atom economy, excellent site-, regio-, and diastereoselectivity, broad substrate scope, and high efficiency. Up to eight new chemical bonds and two carbocycles can be efficiently constructed via this protocol. The utility of this method is well demonstrated by the late-stage elaboration of pharmaceutical molecules and total or formal synthesis of biologically active natural products, such as (±)-β-cuparenone, (±)-laurokamurene B, and (±)-cuparene.

Figure 3.  Radical [3+2] cycloaddition of alkynes with alkyl aldehydes

For more details, especially on the reaction development, substrate scope, and mechanistic studies for this radical [3+2] annulation of internal alkynes, please have a look at our article.

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