Total Synthesis of Pleurotin (Y. Q. Long 2024)

Pleurotin (1, see Fig. 1) is a benzoquinone meroterpenoid that was first isolated in the late 1940s.[1] Since that time, several total syntheses of this compound have been reported. Recently, Ya-Qiu Long and his team from Soochow University (China) published a novel synthetic route in the journal JACS Au.[2] They demonstrated that their divergent synthetic approach allows for the production of sufficient quantities of the advanced intermediate 2, facilitating the synthesis of various analogues through late-stage modifications.

The overall synthetic strategy employed by Long and his team is illustrated in Figure 1. The retrosynthetic analysis begins with the introduction of a lactone ring into intermediate 2 through hydroboration and subsequent allylic oxidation. To obtain the benzoquinone precursor, the researchers utilized an aryl addition followed by a Friedel-Crafts cyclisation, which effectively constructs the desired framework. Ultimately, intermediate 3 can be synthesized from 4 via ring-closing metathesis (RCM) and reduction.

Figure 1: Retrosynthetic approach for the synthesis of pleurotin (1).

Synthesis on Key Intermediate 2

Despite its complexity, the RCM precursor 4 can be synthesized in a single step from a literature known starting material. As illustrated in Figure 2, the copper organyl is prepared in situ by treating compound 5 with tBuLi, followed by transmetallation. This process enables 1,4-addition Michael addition to 6, where the nucleophilic enolate formed is subsequently quenched by the addition of bromide 7, yielding the desired precursor 4 in good yield; however, with low diastereoselectivity, with 4 being the major isomer.

Figure 2: Synthesis of key intermediate 2.

Following this, ring-closing metathesis was performed, succeeded by a diastereoselective reduction to produce compound 3 in good yields. The reduction results in the formation of an alcohol, which is then reoxidized using Dess-Martin periodinane (DMP) to restore the carbonyl functionality. Afterward, the tert-butyldiphenylsilyl (TBPDS) protecting group is removed using HF pyridine, liberating the alcohol, which then cyclises to form the 7-membered lactone 8 through the action of DBU.

The resulting ketone 8 is deprotonated, creating an enolate that is treated with phenyl trifluoromethanesulfonate (PhNTf₂), yielding the vinylic triflate. This intermediate undergoes a Negishi cross-coupling reaction with compound 9, resulting in the formation of product 10 in very good yield. Ultimately, the key intermediate 2 is synthesized by reducing the ester to a hemiacetal, followed by a subsequent Friedel-Crafts cyclisation.

Synthesis of Pleurotin and Analogues

With key intermediate 2 in hand, Long and his colleagues promptly proceeded to synthesize pleurotin (1), as illustrated in Figure 3. The process began with the hydroboration of the double bond, which facilitated subsequent carboxylation. Following this, the benzoquinone structure was liberated through oxidation. A final oxidation step yielded pleurotin (1).

Figure 3: Completion of the total synthesis of 1 and analogues.

Overall, this synthetic route enables the construction of the terpenoid in 14 steps starting from compound 7. The authors also demonstrated the synthesis of several analogues derived from intermediate 2 through late-stage modifications. Notably, some analogues, such as compound 13, exhibited similar or enhanced biological activity compared to their parent compounds, thereby highlighting the potential and versatility of this synthetic approach.

Published in: B. Huang, J. Pang, N. Cao, Y. S. Dai, Y. Q. Long JACS Au 2024. doi: 10.1021/jacsau.4c00942