Intramolecular Diels Research Articles

Asymmetric Total Synthesis of Euphordraculoate A and Pedrolide

AbstractHere we report the asymmetric total syntheses of two rearranged tigliane diterpenoids, euphordraculoate A and pedrolide. A reductive dihydroxylation cascade and Nazarov cyclization were performed to generate euphordraculoate A, which was subjected to a cascade of Eu‐promoted dienyl enolization, intramolecular Diels–Alder reaction and enol‐ketone tautomerization to afford pedrolide, a pathway consistent with our proposal for the biogenesis of pedrolide.

Large Molecular Rotation in Crystal Changes the Course of a Topochemical Diels–Alder Reaction from a Predicted Polymerization to an Unexpected Intramolecular Cyclization

AbstractA designed anthracene‐based monomer for topochemical Diels–Alder cycloaddition polymerization crystallized with head‐to‐tail arrangement of molecules, as revealed by single‐crystal X‐ray diffraction (SCXRD) analysis. The diene and dienophile units of adjacent monomer molecules are aligned at an average distance of 4.6 Å, suggesting a favorable crystalline arrangement for their intermolecular Diels–Alder cycloaddition reaction to form a linear polymer. Surprisingly, heating the monomer crystals at a temperature above 125 °C resulted in the formation of intramolecular Diels–Alder cycloadduct, which could be characterized by various spectroscopy and SCXRD analysis. Various time‐dependent studies such as NMR, PXRD, and DSC, studies established that the reaction followed topochemical pathway. Schmidt's topochemical postulates are generally used to predict the topochemical reactivity and product, by analyzing the crystal structure of the reactant. Though the crystal arrangement predicted polymerization, upon heating, the molecule avoided this pathway by undergoing a large rotation to form an intramolecular cycloadduct. Theoretical calculations supported the feasibility of the rotation, exploiting the flexibility of the molecule and voids present. These findings caution that the reliance on Schmidt's criteria for topochemical reactions may sometimes be misleading, especially in heat‐induced reactions.

Rosellichalasins A–H, cytotoxic cytochalasans from the endophytic fungus Rosellinia sp. Glinf021

Eight new cytochalasans rosellichalasins A–H (1–8), as well as two new shunt metabolites rosellinins A (9) and B (10) before intramolecular Diels–Alder cycloaddition reaction in cytochalasan biosynthesis, along with nine known cytochalsans (11–19) were isolated from the endophytic fungus Rosellinia sp. Glinf021, which was derived from the medicinal plant Glycyrrhiza inflata. Their structures were characterized by extensive analysis of 1D and 2D NMR as well as HRESIMS spectra and quantum chemical ECD calculations. The cytotoxic activities of these compounds were evaluated against four human cancer cell lines including HCT116, MDA-MB-231, BGC823, and PANC-1 with IC50 values ranging from 0.5 to 58.2 μM.

Total Synthesis and Stereochemical Assignment of Talaroconvolutin A and Talarofuranone: Gram‐scale Synthesis of Ferroptosis Inducer Talaroconvolutin A

Comprehensive SummaryThe first total synthesis of talaroconvolutin A (1.1 g obtained) and talarofuranone has been achieved using accessible materials (12 steps, 7.5% and 8.2% yields, respectively). Convergent routes involved intramolecular Diels−Alder reactions in two approaches for creating the decalin moiety. Additionally, an unprecedented DMP‐mediated domino reaction resulted in the deoxy‐tetramic acid system. These syntheses not only establish the absolute configuration of talaroconvolutin A but also enable further collaborative studies of this type of ferroptosis inducers.

Dearomative Intramolecular Diels-Alder/Sulfur Extrusion Reaction of Thiophenes with Alkynes Using peri-Substituted Naphthalene as a Tether.

Dearomative intramolecular Diels-Alder/sulfur extrusion reaction of thiophenes with alkynes successfully afforded fluoranthenes in moderate to excellent yields. The proximity of both reactive sites fixed at the peri-position of naphthalene would play an important role in the progress of this reaction. Tri(o-tolyl)phosphine effectively suppressed the side reactions as a sulfur scavenger.

The short route to chalcogenurea-substituted 3a,6-epoxyisoindoles via an intramolecular Diels–Alder furan (IMDAF) reaction. Antibacterial and antifungal activity

A concise preparative IMDAF strategy for the synthesis of chalcogenurea-substituted 3a,6-epoxyisoindoles, which display antifungal and antibacterial activity, starting from readily available materials was proposed.

Total Synthesis of Lucidumone: Attempted Shortcuts, Dead Ends and Lessons Learnt

AbstractLucidumone is a meroterpenoid isolated from the mushroom Ganoderma lucidum, displaying selective COX-2 inhibitory activity. In this work, we detail our synthetic efforts which led to the first enantioselective synthesis of lucidumone in 13 steps (longest linear sequence). Beyond the key retro-[4+2]/intramolecular Diels–Alder cascade, we discuss the difficulties regarding fragment assembly, introduction of the methyl ketone moiety and choice of adequate protecting group.

Molecular dynamics simulations and machine-learning assisted study of the reaction path bifurcation: Application to the intramolecular Diels–Alder cycloaddition between cyclobutadiene and butadiene

The intramolecular Diels–Alder cycloaddition between cyclobutadiene and butadiene, which involves post-transition-state bifurcation (PTSB), has been investigated using the ring-polymer molecular dynamics (RPMD), classical MD and quasi-classical trajectory (QCT) simulations, and supervised machine-learning (ML) technique. The branching fraction of this reaction strongly depends on the simulation temperature. While QCT, classical MD and RPMD simulations performed at room temperature, starting from the ambimodal transition state (TS), showed the similar dynamics, QCT overestimated the minor branching fraction at low temperature. The supervised machine-learning analysis revealed that the initial coordinates and momenta for low frequency modes at the ambimodal TS contribute to the branching dynamics. The classical MD and RPMD methods follow similar conditions to quantum Boltzmann distributions, whereas the artificially localized phase distribution, considering that the zero-point energy is wedged into the classical particles. As a result, the QCT method can provide inadequate bifurcation dynamics, such as the overestimation of the minor product.

Oxa-di-π-methane Rearrangement of a Substrate Embodying the Platencin Core Provides the Decahydro-1H-cyclopenta[c]indene Framework Associated with Various Diterpenes and Certain Lycopodium Alkaloids

AbstractA chemoenzymatic approach to the title framework is reported. The reaction sequence starts with the whole-cell biotransformation of iodobenzene and the conversion of the resulting homochiral metabolite into a triene that engages in an intramolecular Diels–Alder reaction and so affording an adduct embodying the platencin core. Application of an oxa-di-π-methane rearrangement to a derivative of this core affords a cyclopropannulated form of the target framework; the latter is then obtained through a TMSI-mediated cleavage of the three-membered ring. A strategy for the assembly of the enantiomeric framework is also described.

Synthesis of Diastereomeric 8‐Fluoro‐ABC‐Steroid Building Blocks

AbstractAn eight‐step linear sequence for the preparation of two diastereomers of an 8‐fluoro‐ABC‐steroid building block was developed. Key step was an intramolecular Diels–Alder reaction of an intermediate o‐quinodimethane formed from a benzocyclobutene substituted with a 5‐fluorohex‐5‐en‐4‐one chain. This side chain was prepared from 6‐chlorohex‐1‐ene by bromofluorination, elimination of HBr, Finkelstein reaction and alkylation of a literature‐known benzocyclobutene derivative with the thus‐formed 6‐iodo‐2‐fluorohex‐1‐ene. Allylic oxidation of side chain's fluorovinyl moiety to an α‐fluoro‐α,β‐unsaturated ketone completed the preparation of the precursor for the [4+2]‐cycloaddition.

Retro-[4+2]/Intramolecular Diels–Alder Cascade Allows a Concise Total Synthesis of Lucidumone

AbstractLucidumone is a recently isolated meroterpenoid displaying interesting biological activity. This natural product possesses a complex structure, including a bicyclo[2.2.2]octane possessing 6 contiguous stereogenic centers. Herein, we discuss strategies to solve this synthetic challenge. In particular, we developed a new method for the inverse electron-demand Diels–Alder cycloaddition between 2-pyrones and acyclic enol ethers, as a mean to obtain a ‘masked’ cyclohexadiene. This method allowed an expeditious enantioselective synthesis of (+)-lucidumone through a retro-[4+2]/intramolecular Diels–Alder reaction cascade.1 Introduction2 Retrosynthetic Considerations on the Bicyclo[2.2.2]octane3 Development of a Methodology for Enantioselective IEDDA Cycloadditions4 Enantioselective Total Synthesis of (+)-Lucidumone5 Conclusion

Total Syntheses of (±)-Dracocephalone A and (±)-Dracocequinones A and B.

Described herein are the first total syntheses of (±)-dracocephalone A (1) and (±)-dracocequinones A (4) and B (5). The synthesis was initially envisioned as proceeding through an intramolecular isobenzofuran Diels-Alder reaction, a strategy that eventually evolved into a Lewis acid-promoted spirocyclization. This highly diastereoselective transformation set the stage for trans-decalin formation and a late-stage Suárez oxidation that produced a [3.2.1] oxabicycle suited for conversion to 1. Brønsted acid-mediated aromatization, followed by a series of carefully choreographed oxidations, allowed for rearrangement to a [2.2.2] oxabicycle poised for conversion to 4 and 5.

Total Syntheses of (±)‐Dracocephalone A and (±)‐Dracocequinones A and B

AbstractDescribed herein are the first total syntheses of (±)‐dracocephalone A (1) and (±)‐dracocequinones A (4) and B (5). The synthesis was initially envisioned as proceeding through an intramolecular isobenzofuran Diels–Alder reaction, a strategy that eventually evolved into a Lewis acid‐promoted spirocyclization. This highly diastereoselective transformation set the stage for trans‐decalin formation and a late‐stage Suárez oxidation that produced a [3.2.1] oxabicycle suited for conversion to 1. Brønsted acid‐mediated aromatization, followed by a series of carefully choreographed oxidations, allowed for rearrangement to a [2.2.2] oxabicycle poised for conversion to 4 and 5.

Total Synthesis of Yuzurine-type Alkaloid Daphgraciline.

The first total synthesis of daphgraciline has been achieved, which also represents the first example of the synthesis of Daphniphyllum yuzurine-type alkaloids (∼50 members). The unique bridged azabicyclo[4.3.1] ring system in the yuzurine-type subfamily was efficiently and diastereoselectively assembled via a mild type II [5+2] cycloaddition for the first time. The compact tetracyclic [6-7-5-5] skeleton was installed efficiently via an intramolecular Diels-Alder reaction, followed by a benzilic acid-type rearrangement. The synthetically challenging spiro tetrahydropyran moiety in the final product was installed diastereoselectively via a TiIII-mediated reductive epoxide coupling reaction. Potential access to enantioenriched daphgraciline is presented.

A Regio‐ and Diastereoselective Stille Coupling/Intramolecular Diels–Alder Cascade for the Generation of Fused Pyridines and Application in the Synthesis of (+)‐Lycopladine A and (−)‐Lycoposerramine R

2-Pyrones with a chiral branched allylic silyl ether substituent underwent intramolecular Diels–Alder reactions with remarkably high π-facial- and endo-selectivities. The resulting diastereomerically and enantiomerically pure cycloadducts were transformed into the natural products (+)-lycopladine A and (−)-lycoposerramine R.

Total Synthesis of (+)‐Alstonlarsine A

An enantioselective total synthesis of (+)-alstonlarsine A (1), a monoterpenoid indole alkaloid possessing a unique pentacyclic skeleton as well as a rare biological activity, is achieved. The key step is an efficient domino sequence, comprising enamine formation followed by an inverse-electron-demand intramolecular dearomative Diels–Alder cycloaddition for the construction of 9-azatricyclo[4.3.1.03,8]decane core. The key intermediate for this domino sequence was synthesized by a newly developed methodology, relying on indole C(2)-H bond functionalization, combined with intramolecular Horner–Wadsworth–Emmons reaction. This tactical combination offers a new general entry into other (privileged) tricyclic frameworks possessing indole ring fused to 6-, 7- or 8-membered rings.

Biosynthesis of Sordarin by an Intramolecular Diels–Alder Reaction Catalyzed by a Novel Diels–Alderase

Biosynthesis of Sordarin by an Intramolecular Diels–Alder Reaction Catalyzed by a Novel Diels–Alderase

Total Synthesis of Ophiorrhine A, G and Ophiorrhiside E Featuring a Bioinspired Intramolecular Diels–Alder Cycloaddition**

AbstractWe report the first total synthesis of the monoterpene indole alkaloids ophiorrhine A via a late stage bioinspired intramolecular Diels–Alder cycloaddition to form the intricate bridged and spirannic polycyclic system. Several strategies were investigated to construct the indolopyridone moiety of ophiorrhiside E, the postulated biosynthetic precursor of ophiorrhine A. Eventually, the Friedel–Crafts‐type coupling of N‐methyl indolyl‐acetamide with a secologanin‐derived acid chloride delivered ophiorrhine G. Cyclodehydration of a protected form of the latter was followed by the desired spontaneous intramolecular Diels–Alder cycloaddition of protected ophiorrhiside E leading to ophiorrhine A.

Synthetic Studies toward Australifungin

AbstractAs a fungal metabolite, australifungin possesses an α-diketone and a β-ketoaldehyde moiety on its trans-decalin backbone. Microwave-assisted intramolecular Diels–Alder reaction was used as a key strategy to establish the trans-decalin moiety. Further functionalization of the ring B side chain installed the β-ketoaldehyde, one of the two unique functional groups along with the α-diketone.

Biosynthesis of Sordarin Revealing a Diels–Alderase for the Formation of the Norbornene Skeleton

AbstractSordarin (1) is a fungal diterpene glycoside that displays potent antifungal bioactivity through inhibition of elongation factor 2. The structures of sordarin and related compounds feature a highly rearranged tetracyclic diterpene core. In this study, we identified a concise pathway in the biosynthesis of sordarin. A diterpene cyclase (SdnA) generates the 5/8/5 cycloaraneosene framework, which is decorated by a set of P450s that catalyze a series of oxidation reactions, including hydroxylation, desaturation, and C−C bond oxidative cleavage, to give a carboxylate intermediate with a terminal alkene and a cyclopentadiene moiety. A novel Diels–Alderase SdnG catalyzes an intramolecular Diels–Alder (IMDA) reaction on this intermediate to forge the sordarin core structure. Subsequent methyl hydroxylation and glycosylation complete the biosynthesis of sordarin. Our work discloses a new strategy used by nature for the formation of the rearranged diterpene skeleton.