The Dötz Benzannulation Reaction: A Booming Methodology for Natural Product Synthesis

Bera, Turban; Pandey, Kartikey; Ali, Rashid

doi:10.1002/slct.202000514

Cited by 10 publications

(4 citation statements)

References 97 publications

(102 reference statements)

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“…With the D- and A-ring building blocks 5 and 6 in hand, we embarked on the C-ring construction via Dötz benzannulation ( Scheme 1c ). 28 The annulation was followed by 2,3-dichloro-5,6-dicyano-benzoquinone (DDQ) oxidation to give the A-ring tethered naphthalene-1,4-dione 14; which through Na 2 S 2 O 4 reduction and acetylation was converted to the A-ring tethered naphthalene-1,4-diacetate 15. Subsequent acetate-assisted intramolecular directed arylation enabled construction of the B-ring in a highly congested environment.…”

Section: Resultsmentioning

confidence: 99%

Total synthesis of landomycins Q and R and related core structures for exploration of the cytotoxicity and antibacterial properties

Lai

Mondal

et al. 2021

RSC Adv.

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Section: Resultsmentioning

confidence: 99%

Total synthesis of landomycins Q and R and related core structures for exploration of the cytotoxicity and antibacterial properties

Lai

Mondal

et al. 2021

RSC Adv.

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“…Morken’s double allylation in the asymmetric synthesis of pumilaside aglycon, Carreira’s cyclohexyne-based annulation en route to guanacastepenes, Pronin’s forskolin synthesis leveraging a radical/polar crossover annulation, and Dong’s enantioselective annulation by C–C bond activation to access the alkaloid cycloclavine all beautifully leverage annulative processes as key steps . Many of these tandem processes have been made possible through advances in asymmetric synthesis, contemporary radical chemistry, and methods for inert bond functionalizationall cutting-edge synthetic areas with annulative potential. ,,,, We fully suspect this trend of advancement to continue, heralding powerful new annulations and ultimately improved synthetic pathways to complex polycyclic natural products.…”

Section: Discussionmentioning

confidence: 99%

“…Throughout the 20th century, a variety of powerful annulation reactions, particularly those forming two C–C bonds, have been strategically employed in problems in total synthesis including Robinson’s classic synthesis of cholesterol employing a polar, anionic annulation, , Stork’s synthesis of cantharidin featuring an early application of the Diels–Alder reaction, , Curran’s radical annulation-based synthesis of albene, , and Trost’s synthesis of loganin aglycone leveraging a transition metal-catalyzed annulation (Figure ). , While these annulations all serve the general goal of forming a new ring, the diversity of the reaction mechanisms and reactive intermediates involved is both distinct and notable.…”

Section: Introductionmentioning

confidence: 99%

Annulative Methods in the Synthesis of Complex Meroterpene Natural Products

et al. 2021

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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...

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“…To the best of our knowledge, the current review is the first to focus exclusively on the participation of FCCs in the following higher‐order cycloadditions: [2+2+2+1], [3+2+2], [3+3], [4+2+1], [4+3], [5+2], [5+2+1], [6+2], [6+3], [8+2] and [8+3]. Although the Dötz reaction is regarded a higher‐order cycloaddition, it does not fall within the scope of the present review, [62–65] which focuses on all higher‐order reactions involving more than 6π electrons or over 6 atoms. A great effort was made not to omit any relevant information in the literature.…”

Section: Introductionmentioning

confidence: 99%

Fischer Carbene Complexes: A Glance at Two Decades of Research on Higher‐Order Cycloaddition Reactions

Feliciano

Vázquez

Benítez‐Puebla

et al. 2021

Chemistry A European J

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The structure of Fischer carbene complexes (FCCs) is electron deficient. If bearing an α,β‐unsaturated system, it can generate a wide variety of compounds by undergoing many different transformations, including higher‐order cycloadditions. The latter are described as pericyclic reactions in which more than six electrons participate. These reactions have been employed in various areas of organic synthesis, resulting in highly selective compounds with a broad range of scaffolds. The first studies on higher‐order cycloadditions involving FCCs frequently yielded competing byproducts. Many groups have attempted to increase selectivity by exploring distinct reaction conditions, reagents and co‐catalysts (e. g., metal‐mediated cycloadditions). The present review is the first to focus exclusively on using higher‐order cycloadditions involving FCCs to synthesize carbocycles and heterocycles. Based on two decades of reports, an analysis is made of the main aspects of the mechanisms proposed for higher‐order cycloadditions and the structural diversity obtained by the substituent effect.

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The Dötz Benzannulation Reaction: A Booming Methodology for Natural Product Synthesis

Cited by 10 publications

References 97 publications

Total synthesis of landomycins Q and R and related core structures for exploration of the cytotoxicity and antibacterial properties

Total synthesis of landomycins Q and R and related core structures for exploration of the cytotoxicity and antibacterial properties

Annulative Methods in the Synthesis of Complex Meroterpene Natural Products

Fischer Carbene Complexes: A Glance at Two Decades of Research on Higher‐Order Cycloaddition Reactions

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