Synthesis of Multisubstituted Silyloxy‐based Donor‐Acceptor Cyclobutanes by an Acid‐Catalyzed [2+2] Cycloaddition

Abstract

This account summarizes our recent efforts on the acid‐catalyzed [2+2] cycloaddition of silyl enol ethers with α,β‐unsaturated esters, giving donor‐acceptor (D‐A) cyclobutanes and their related reactions. The cycloaddition generally produces multisubstituted cyclobutanes in good yields with high diastereoselectivity. We found that aluminum Lewis acids and triflic imide (Tf2NH) had good catalytic activity. The retro [2+2] cycloaddition proceeded at higher reaction temperatures, and in some cases, diastereoselectivity switching of cycloadducts was observed. A microflow protocol was established for Tf2NH‐catalyzed [2+2] cycloaddition. Although the cycloaddition usually requires cryogenic conditions in a batch reactor, the microreactor system enabled the production of D‐A cyclobutanes, even at ambient temperature. [2+2] Cycloaddition of allylsilanes and alkyl enol ethers, instead of silyl enol ethers, afforded the corresponding D‐A cyclobutanes.

Recent advances in the total synthesis of cyclobutane-containing natural products

“…Takasu and co-workers have made great efforts on the triflic imide (Tf 2 NH) catalyzed [2 + 2] cycloaddition reactions of silyl enol ethers for the construction of various fused cyclobutane rings bearing a silyloxy group at the bridgehead position. 56 This effective method has been successfully applied to the synthetic studies toward penitrems, a family of indole diterpene alkaloids isolated from Penicillium cyclopium and Penicillium crustosum with strong neurotoxicity. 57 Most recently, the same group reported the first total synthesis of cytotoxic paesslerin A (146) through a Tf 2 NH-catalyzed multicomponent reaction between cyclopentenone 140, 2-siloxy-butadiene 141 and methyl acrylate 144 (Scheme 21).…”

Ring-Opening Reactions of Donor–Acceptor Cyclobutanes with Electron-Rich Arenes, Thiols, and Selenols

“…Second, the preparation of the four-membered ring precursors is not as straightforward as the [2 + 1]-cycloaddition leading to the respective cyclopropanes. Typical syntheses of these derivatives occur by formal [2 + 2]-cycloadditions or via substitution reactions of a 1,3-disubstituted precursor with, for example, a malonic acid diester . Nevertheless, few groups have utilized D–A cyclobutanes for their transformations, especially for the assembly of heterocyclic compounds .…”

Triflimide (HNTf2) in Organic Synthesis

“…In the past decade, triflimide has been demonstrated to be a uniquely effective catalyst or precatalyst for a range of [2 + 2] cycloaddition reactions, complementing not only Lewis acids but also other commonly used Brønsted acids. 40 In 2005, Inanaga, Takasu, and Ihara reported the first example of HNTf 2 -catalyzed efficient [2 + 2] cycloaddition of silyl enol ethers with α,β-unsaturated esters (Scheme 3). 41 With 1 mol % of HNTf 2 , the reaction proceeded smoothly even at −78 °C to form the corresponding cyclobutane with both good chemical yield and excellent stereoselectivity.…”

“…In these reactions, photochemical and thermal [2 + 2] cycloadditions have been known to be effective, but it often remains challenging to control both reactivity and selectivity. In the past decade, triflimide has been demonstrated to be a uniquely effective catalyst or precatalyst for a range of [2 + 2] cycloaddition reactions, complementing not only Lewis acids but also other commonly used Brønsted acids …”