Two Steps to Bicyclo[4.2.0]octadienes from Cyclooctatetraene: Total Synthesis of Kingianic Acid A

Patel, Harshal D.; Fallon, Thomas

doi:10.1021/acs.orglett.2c00325

Org. Lett.

2022

DOI: 10.1021/acs.orglett.2c00325

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Two Steps to Bicyclo[4.2.0]octadienes from Cyclooctatetraene: Total Synthesis of Kingianic Acid A

Harshal D. Patel

Thomas Fallon

Abstract: Synthetic approaches to bicyclo[4.2.0]octadiene natural products frequently employ the synthesis of linear tetraenes to initiate a biosynthetic 8π/6πelectrocyclization cascade. This work forges a functionalized bicyclo[4.2.0]octadiene in two steps from cyclooctatetraene. The versatility of this method is demonstrated through natural product synthesis, including the first total synthesis of kingianic acid A and formal syntheses of kingianins A, D, and F and cryptobeilic acid D ethyl ester. The unexpected format… Show more

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Cited by 3 publications

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Bioinspired Asymmetric Total Synthesis of Emeriones A–C**

Jänner

Isak

et al. 2022

Angewandte Chemie

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We report asymmetric bioinspired total syntheses of the fungal metabolites emeriones A-C via stereoselective oxidations of two bicyclo[4.2.0]octadiene diastereomers. The central bicyclic scaffolds are prepared in an 8π/6π electrocyclization cascade of a stereodefined pentaene, which contains the fully assembled side chains of the emeriones. The anti-aldol side chain is made using a Paterson-aldol addition, and the epoxide of the dioxabicyclo[3.1.0]hexane side chain via ring-closure onto an oxidized acetal. Our work has enabled the structural revision of emerione C, and resulted in the synthesis of a "missing" family member, which we call emerione D. DFT calculations identified two methyl groups that govern torquoselectivity in the 8π/6π cascade.Natural products derived from polyenes that undergo cyclization/isomerization cascades initiated by an 8π electrocyclization have intrigued chemists for decades. [1] The emeriones (Figure 1), one such family of natural products that were isolated from the fungus E. nidulans, [2] display oxidized bicyclo[4.2.0]octadiene cores (red) flanked by a seven carbon aldol fragment (blue) and a propenyl-substituted dioxabicyclo[3.1.0]hexane system (black). The two side chains (blue and black) of emerione A (1) and B (2) share the same absolute configurations, while the bicyclo-[4.2.0]octadieneoxide central scaffolds are enantiomeric with respect to each other. Emerione C has a bridging endoperoxide on the central core, and its proposed structure has a stereochemical configuration similar to emerione B.Related substances like shimalactone A (3) [1p] and ocellapyrone B (4) [1m, n] have been synthesized, but the emeriones are arguably the most complex examples of such natural products, each containing twelve stereocenters, eight of which are contiguous, and two quaternary. Moreover, the dioxabicyclo[3.1.0]hexane system, also found in natural products like verrucosidin (5), [3] is a considerable synthetic challenge alongside the oxidized bicyclo[4.2.0]octadiene scaffolds. Emerione A inhibits NO production in lipopolysaccharide-induced RAW264.7 cells [2] as well as NDM-1 [4] at low micromolar concentrations, but the emeriones appear not to have been tested in other assays. Motivated both by their striking structures and potentially undiscovered bioactivities, we chose to target the emeriones for synthesis. We describe herein the successful completion of the syntheses, the structural revision of emerione C, and the synthesis of the originally proposed structure of emerione C, which we name emerione D.

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Bioinspired Asymmetric Total Synthesis of Emeriones A–C**

Jänner

Isak

et al. 2022

Angewandte Chemie

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Bioinspired Asymmetric Total Synthesis of Emeriones A–C**

Jänner

Isak

et al. 2022

Angew Chem Int Ed

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Total Synthesis and Structural Revision of the 6,11-Epoxyisodaucane Natural Sesquiterpene Using an Anionic 8π Electrocyclic Reaction

et al. 2022

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A new synthetic strategy that forms a seven-membered carbocycle using an anionic 8π electrocyclic reaction facilitated the first total synthesis of the 6,11-epoxyisodaucane natural sesquiterpene in 9.0% yield over 10 steps in the longest linear sequence. The misassigned proposed stereochemistry was corrected by the synthesis of both the proposed structure and its C6 epimer. In addition, the 5-7-fused ring system was concisely constructed by tandem decyanation/five-membered-ring formation from an epoxynitrile.

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Two Steps to Bicyclo[4.2.0]octadienes from Cyclooctatetraene: Total Synthesis of Kingianic Acid A

Cited by 3 publications

References 62 publications

Bioinspired Asymmetric Total Synthesis of Emeriones A–C**

Bioinspired Asymmetric Total Synthesis of Emeriones A–C**

Bioinspired Asymmetric Total Synthesis of Emeriones A–C**

Total Synthesis and Structural Revision of the 6,11-Epoxyisodaucane Natural Sesquiterpene Using an Anionic 8π Electrocyclic Reaction

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