Total Synthesis of (±)-Berkeleyone A

Abstract

A 13-step total synthesis of the fungal meroterpenoid berkeleyone A is reported. The molecular skeleton is formed using the first examples of two critical construction reactions: (1) an epoxide-initiated, β-ketoester-terminated polycyclization, and (2) an isomerization-cyclization cascade to generate the remaining bicyclo[3.3.1]nonane framework. The resulting 6-step synthesis of the carbocyclic core of the berkeleyone natural products has been used to access protoaustinoid A and berkeleyone A, and will aid future biosynthetic investigations into the origin of related natural products.

Genome Mining and Comparative Biosynthesis of Meroterpenoids from Two Phylogenetically Distinct Fungi

“…[10,11] Taking advantage of this,w ea ttempted to discover new PK-TP meroterpenoids through genome mining using PKS,P T, and CT probes,w hich led us to identify two homologous meroterpenoid BGCs from two phylogenetically distinct fungi. Both strains were then cultivated in various media, which led to the production of produced ten related meroterpenoids (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). Based on bioinformatics and genetic and biochemical analysis,w ep ropose biosynthetic pathways for 1-10.…”

Catalytic Enantioselective Formal (4+2) Cycloaddition by Aldol–Aldol Annulation of Pyruvate Derivatives with Cyclohexane‐1,3‐Diones to Afford Functionalized Decalins

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The decalin structure is found in bioactive molecules.W eh ave developed catalytic enantioselective formal (4+ +2) cycloaddition reactions via aldol-aldol cascade reactions between pyruvate-derived diketoester derivatives and cyclohexane-1,3-dione derivatives that affordh ighly functionalized decalin derivatives.The reactions were performed using aq uinidine-derived catalyst under mild conditions.D ecalin derivatives bearing up to six chiral carbon centers including tetrasubstituted carbon centers were synthesized with high diastereo-and enantioselectivities.F ive to six stereogenic centers were generated from achiral molecules with the formation of two C À Cb onds in as ingle transformation resulting in the formation of the decalin system. [2][3][4][5] Construction of the decalin ring system has been performed using cycloadditions, [2] cross coupling, [3] polyene cyclizations and related ene-involved annulations, [4] Robinson annulations [2c,d, 5] and related Michael-aldol reactions, [6] in which the reactions start from Michael additions to a,b-unsaturated ketones.H ere we report organocatalytic enantioselective aldol-aldol annulation cascade reactions to afford functionalized decalin derivatives (Scheme 1).In our strategy,C2symmetric starting materials pyruvatederived diketoester derivatives (dihydropyran derivatives) 1 [7] and cyclohexane-1,3-diones 2 are used for the aldol-aldol annulation cascade reactions to construct new cyclohexane rings,r esulting in the formation of decalin derivatives 3 or 4 (Scheme 1). [1] Decalin derivatives often have antiinflammatory,a nti-bacterial, and anti-tumor activities.

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Traversing Biosynthetic Carbocation Landscapes in the Total Synthesis of Andrastin and Terretonin Meroterpenes

“…[1] These meroterpenes, while historically the subject of intense biosynthetic interest, [1,2] have only very recently seen members succumb to total synthesis efforts. [3] The andrastins (see 1 – 6 ), [2l,4] terretonins (see 10 – 15 ), [2i,5,6] and their downstream congeners in particular, represent a large subset of DMOA-derived members with interesting biological profiles and unique carbocyclic frameworks (Figure 1). [1] To date these compounds have evaded successful chemical synthesis attempts.…”

“…recently prepared protoaustinoid A ( 18 ) en route to distinct total syntheses of berkeleyone A. [3] While these pathways did not directly proceed through carbocation 17 , we wondered if 18 (or a suitable synthetic surrogate) could be “reverted” to the andrastin and terretonin ring systems directly in the absence of enzymes, possibly driven by a thermodynamic preference for 5 and/or 8 . If feasible, this could potentially open up synthetic access to nearly half of the remaining DMOA-derived members believed to proceed through carbocation 17 .…”

“…[11,12] Substrate 21 was prepared in one-step from tetracyclic building block 20 , an intermediate we have prepared in gram quantities en route to the synthesis of berkeleyone A (Scheme 1). [3a] Subjecting 21 to modified Shigehisa conditions (cat. Co(II), PhSiH 3 , N -fluoropyridinium salt (F + ) oxidant) yet omitting the alcohol trapping agent cleanly promoted the desired rearrangement.…”