Annulative Methods in the Synthesis of Complex Meroterpene Natural Products

Abstract

Conspectus From the venerable Robinson annulation to the irreplaceable Diels–Alder cycloaddition, annulation reactions have fueled the progression of the field of natural product synthesis throughout the past century. In broader terms, the ability to form a cyclic molecule directly from two or more simpler fragments has transformed virtually every aspect of the chemical sciences from the synthesis of organic materials to bioconjugation chemistry and drug discovery. In this Account, we describe the evolution of our meroterpene synthetic program over the past five years, enabled largely by the development of a tailored anionic annulation process for the synthesis of hydroxylated 1,3-cyclohexanediones from lithium enolates and the reactive β-lactone-containing feedstock chemical diketene. First, we provide details on short total syntheses of the prototypical polycyclic polyprenylated acylphloroglucinol (PPAP) natural products hyperforin and garsubellin A, which possess complex bicyclo[3.3.1]­nonane architectures. Notably, these molecules have served as compelling synthetic targets for several decades and induce a number of biological effects of relevance to neuroscience and medicine. By merging our diketene annulation process with a hypervalent iodine-mediated oxidative ring expansion, bicyclo[3.3.1]­nonane architectures can be easily prepared from simple 5,6-fused bicyclic diketones in only two chemical operations. Leveraging these two key chemical reactions in combination with various other stereoselective transformations allowed for these biologically active targets to be prepared in racemic form in only 10 steps. Next, we extend this strategy to the synthesis of complex fungal-derived meroterpenes generated biosynthetically from the coupling of 3,5-dimethylorsellinic acid (DMOA) and farnesyl pyrophosphate. A Ti­(III)-mediated radical cyclization of a terminal epoxide was used to rapidly prepare a 6,6,5-fused tricyclic ketone which served as an input for our annulation/rearrangement process, ultimately enabling a total synthesis of protoaustinoid A, an important biosynthetic intermediate in DMOA-derived meroterpene synthesis, and its oxidation product berkeleyone A. Through a radical-based, abiotic rearrangement process, the bicyclo[3.3.1]­nonane cores of these natural products could again be isomerized, resulting in the 6,5-fused ring systems of the andrastin family and ultimately delivering a total synthesis of andrastin D and preterrenoid. Notably, these isomerization transformations proved challenging when employing classic, acid-induced conditions for carbocation generation, thus highlighting the power of radical biomimicry in total synthesis. Finally, further oxidation and rearrangement allowed for access to terrenoid and the lactone-containing metabolite terretonin L. Overall, the merger of annulative diketene methodology with an oxidative rearrangement transformation has proven to be a broadly applicable strategy to synthesize bicyclo[3.3.1]­nonane-containing natural products, a class of small molecules w...

Taming Shapeshifting Anions: Total Synthesis of Ocellatusone C

“…Bridged bicyclononane carbon frameworks are a privileged structural motif found in over 1000 natural productsmany with therapeutic relevance to human disease (Figure a). − Our research group has a longstanding interest in the synthesis of natural products containing the bridged bicyclo[3.3.1]­nonane core. , In this context, synthetic endeavors toward these molecular architectures have largely paralleled, or been inspired by, biosynthesisoften first installing substituents, and then constructing the core at a later stage (Figure b). Indeed, this synthetic blueprint has culminated in notable syntheses of many complex bicyclo[3.3.1]­nonane-containing natural products. , As a departure from this synthetic logic, we aimed to develop a divergent synthetic strategy to incorporate side chain fragments about the bicyclo[3.3.1]­nonane core at a late stage.…”

Recent Advances in Chemistry and Antioxidant/Anticancer Biology of Monoterpene and Meroterpenoid Natural Product

“…Hyperforin-like structures are a large family of meroterpenes that share a challenging molecular caged motif. A recent innovative synthetic strategy based on an annulative approach of polycyclic polyprenylated acylphloroglucinol (PPAP) meroterpenoids with 3,5-dimethylorsellinic (DMOA) was reported as shown in Scheme 5 [ 73 ]. The synthesis commenced with the readily available methylcyclopenenone synthon, which was subjected to sequential 1,4-copper-mediated conjugate addition reaction, namely formation of the lithium enolate followed by alkylative enolate trapping to generate the substituted cyclopetanone 37 , which was subjected to further α-alkylated to furnish the highly substituted cyclopetanone 38 .…”

“…A similar approach has been applied to the caged meroterpenoid garsubellin A ( 104, Scheme 6 ) [ 73 ]. The total synthesis was initiated with methylcyclopenenone, which was α-prenylated to generate compound 47 , followed by 1,2 Grignard reaction to access allylic alcohol 48 .…”

Enantioselective Total Synthesis of (−)-Caulamidine A

“…Hexacyclic enamine 10 in turn could arise from the stereoselective coupling of tetracycle 12 and a benzyl halide (see 11 ). Finally, we sought to develop an annulative process to merge dianion 13 and a suitable two-carbon bis-electrophile to generate tetracycle 12 while remaining cognizant of regio- and stereoselectivity concerns during such a process . Herein, we explore elements of this blueprint, culminating in the first total synthesis of caulamidine A ( 1 ) in 11 steps, rigorously confirming both its structure and its absolute configuration.…”