Modular total syntheses of trans-clerodanes and sesquiterpene (hydro)quinones via tail-to-head cyclization and reductive coupling strategies

Abstract

The trans-clerodanes and sesquiterpene (hydro)quinones are a growing class of natural products that exhibit a wide range of biological activities. Although they are different types of natural products, some of them feature the same trans-decalin core structure. Here, we report the total syntheses of two members of trans-clerodanes, five members of sesquiterpene (hydro)quinones as well as the proposed structure of dysidavarone D via a modular synthetic route. A bioinspired tail-to-head cyclization strategy was developed to syntheses of the trans-decalin architectures by using two diastereochemically complementary radical polyene cyclization reactions catalyzed by Ti(III) and mediated by Mn(III), respectively. The different types of side chains were introduced by challenging nickel catalyzed reductive couplings of sterically hindered alkyl halides. The synthesis of the proposed dysidavarone D proved a wrong structural assignment of the natural product.

The Total Synthesis of Mollanol A by a Convergent Strategy

“…We thought that a design logic involving the connection of two fragments featuring most of the important chiral centers and nearly all the essential oxidation states of the natural product in a convergent strategy could reduce the need for late-stage stereocontrol steps and redox steps. 12 A retrosynthetic analysis based on this idea was then performed, as shown in Scheme 1 . Mollanol A was disconnected to a multisubstituted cyclopentene fragment 9 and a bicyclo[3.2.1]octane fragment 10 .…”

Practical and Scalable Total Syntheses of (+)-Dysidavarones A–C

“…3 In 2016 and 2021, the groups of Shen and Qin achieved total syntheses of dysidavarones A and C (1 and 3) by using the same strategy as Menche, but with different benzylic bromides. 4,5 In 2022, Yang and co-workers developed a tail-to-head cyclization strategy for the synthesis of the trans-decalin unit, introducing the side-chain by nickel-catalyzed reductive coupling, to achieve divergent total syntheses of dysidavarones A-C. 6 In 2023, we also completed divergent total syntheses of dysidavarones A-C by a one-pot intermolecular diastereoselective alkylation and intramolecular arylation reaction of a Wieland-Miescher ketone derivative without the protection of the C4 carbonyl group and a benzylic bromide to establish the central bridged bicyclo[3.3.1]nonane ring and a late-stage introduction of the ethyl group onto the key common intermediate predysidavarone. 7 However, the synthetic routes of Menche, Katoh, Shen, and Qin all involved a steric-hindrance-sensitive reductive alkylation reaction of a Wieland-Miescher ketone derivative in liquid ammonia.…”

“…[3] In 2016 and 2021, Shen and Qin's groups achieved the total synthesis of dysidavarones A and C (1 and 3) using the same strategy as Menche's with different benzyl bromides. [4,5] In 2022, Yang and co-workers developed a tail-to-head cyclization strategy for the synthesis of the trans-decalin unit, introduced the side chain by nickel-catalyzed reductive coupling, and achieved the divergent total synthesis of dysidavarones A-C. [6] In 2023, we also completed the divergent total synthesis dysidavarones A-C by a one-pot intermolecular diastereoselective alkylation and intramolecular arylation reaction of a Wieland-Miescher ketone This article is protected by copyright. All rights reserved.…”

“…4 5 In 2022, Yang and co-workers developed a tail-to-head cyclization strategy for the synthesis of the trans -decalin unit, introducing the side-chain by nickel-catalyzed reductive coupling, to achieve divergent total syntheses of dysidavarones A–C. 6 In 2023, we also completed divergent total syntheses of dysidavarones A–C by a one-pot intermolecular diastereoselective alkylation and intramolecular arylation reaction of a Wieland–Miescher ketone derivative without the protection of the C4 carbonyl group and a benzylic bromide to establish the central bridged bicyclo[3.3.1]nonane ring and a late-stage introduction of the ethyl group onto the key common intermediate predysidavarone. 7…”

Enantioselective and collective total synthesis of pentacyclic 19-nor-clerodanes

“…6 Consequently, the total synthesis of clerodanoids has attracted extensive attention from the synthetic community for decades. 7 Among these molecules, pentacyclic 19- nor -clerodanes are attractive synthetic targets owing to their intriguing structures, which feature a compact and densely-functionalized decalin core, a spiro γ-lactone unit, and a fused α,β-unsaturated-γ-lactone moiety (Fig. 1).…”