A Dioxane Template for Highly Selective Epoxy Alcohol Cyclizations

Ladder polyether natural products are a class of natural products denoted by their high functional‐group density and large number of well‐defined stereocenters. They comprise the toxic component of harmful algal blooms (HABs), having significant negative economic and environmental ramifications. However, their mode of action, namely blocking various cellular ion channels, also denotes their promise as potential anticancer agents. Understanding their potential mode of biosynthesis will not only help with developing ways to limit the damage of HABs, but would also facilitate the synthesis of a range of analogs with interesting biological activity. 1,3‐Dioxan‐5‐ol substrates display remarkable ‘enhanced template effects’ in water‐promoted epoxide cyclization processes en route to the synthesis of these ladder polyether natural products. In many cases, they provide near complete endo‐to‐exo selectivity in the cyclization of epoxy alcohols, thereby strongly favoring the formation of tetrahydropyran (THP) over tetrahydrofuran (THF) rings. The effects of various Brønsted and Lewis acidic and basic conditions are explored to demonstrate the superior selectivity of the template over the previously reported THP‐based epoxy alcohols. In addition, the consideration of other synthetic routes are also considered with the goal of gaining rapid access to a plethora of potential starting materials applicable towards the synthesis of ladder polyethers. Finally, cascade sequences with polyepoxides are investigated, further demonstrating the versatility of this new reaction template.     

Evidence that epoxide-opening cascades promoted by water are stepwise and become faster and more selective after the first cyclization

A detailed kinetic study of the endo-selective epoxide-opening cascade reaction of a diepoxy alcohol in neutral water was undertaken using (1)H NMR spectroscopy. The observation of monoepoxide intermediates resulting from initial endo and exo cyclization indicated that the cascade proceeds via a stepwise mechanism rather than through a concerted one. Independent synthesis and cyclization of these monoepoxide intermediates demonstrated that they are chemically and kinetically competent intermediates in the cascade. Analysis of each step of the reaction revealed that both the rate and regioselectivity of cyclization improve as the cascade reaction proceeds. In the second step, cyclization of an epoxy alcohol substrate templated by a fused diad of two tetrahydropyran rings proceeds with exceptionally high regioselectivity (endo:exo = 19:1), the highest we have measured in the opening of a simple trans-disubstituted epoxide. The origins of these observations are discussed.     

Biomimetic synthesis of trans,syn,trans-fused polyoxepanes: remarkable substituent effects on the endo-regioselective oxacyclization of polyepoxides

The biogenesis of trans,syn,trans-fused polycyclic ether substructures of neurotoxic natural products of the brevetoxin-ciguatoxin family may involve regio- and stereoselective oxacyclizations of polyepoxides. We report that a biomimetic Lewis acid-promoted cyclization of 1 to 2 proceeds with endo-regioselectivity and anti-stereospecificity at each position of nucleophilic addition (C3, C7, C11, and C15 in 1) when the tandem cyclization cascade is terminated by a carbonyl oxygen nucleophile. In contrast to expectations from earlier reports with simpler epoxide substrates, alkyl substituents are not required at internal epoxide positions corresponding to C7 and C11 in polyepoxide 1. Furthermore, we report that trimethylsilyl serves as a removable regioselectivity-directing substituent at positions corresponding to C3 of 1. These results greatly expand the potential applications of this biomimetic oxacyclization cascade to the synthesis of fused polycyclic ether natural products.     

Stereoselective Synthesis of (+)‐Petromyroxol

The stereoselective total synthesis of (+)‐petromyroxol, isolated from the water conditioned with the larval sea lamprey has been accomplished by employing the cross‐metathesis, tandem Sharpless asymmetric dihydroxylation/S_N2 cyclization, and regioselective ring opening of epoxide as the key steps.     

Pnictogen-Bonding Catalysis: An Interactive Tool to Uncover Unorthodox Mechanisms in Polyether Cascade Cyclizations

Pnictogen-bonding catalysis and supramolecular σ-hole catalysis in general is currently being introduced as the non-covalent counterpart of covalent Lewis acid catalysis. With access to anti-Baldwin cyclizations identified as unique characteristic, pnictogen-bonding catalysis appeared promising to elucidate one of the hidden enigmas of brevetoxin-type epoxide opening polyether cascade cyclizations, that is the cyclization of certain trans epoxides into cis-fused rings. In principle, a shift from S_N2- to S_N1-type mechanisms could suffice to rationalize this inversion of configuration. However, the same inversion could be explained by a completely different mechanism: Ring opening with C−C bond cleavage into a branched hydroxy-5-enal and the corresponding cyclic hemiacetal, followed by cascade cyclization under conformational control, including stereoselective C−C bond formation. In this report, a pnictogen-bonding supramolecular Sb^V catalyst is used to demonstrate that this unorthodox polyether cascade cyclization mechanism occurs.     

Polyether Natural Product Inspired Cascade Cyclizations: Autocatalysis on π‐Acidic Aromatic Surfaces

Anion‐π catalysis functions by stabilizing anionic transition states on aromatic π surfaces, thus providing a new approach to molecular transformation. The delocalized nature of anion–π interactions suggests that they serve best in stabilizing long‐distance charge displacements. Aiming therefore for an anionic cascade reaction that is as charismatic as the steroid cyclization is for conventional cation‐π biocatalysis, reported here is the anion‐π‐catalyzed epoxide‐opening ether cyclizations of oligomers. Only on π‐acidic aromatic surfaces having a positive quadrupole moment, such as hexafluorobenzene to naphthalenediimides, do these polyether cascade cyclizations proceed with exceptionally high autocatalysis (rate enhancements k_auto/k_cat >10⁴ m ^?1). This distinctive characteristic adds complexity to reaction mechanisms (Goldilocks‐type substrate concentration dependence, entropy‐centered substrate destabilization) and opens intriguing perspectives for future developments.     

Total Synthesis of the Antibiotic Kendomycin: A Macrocyclization Using the Tsuji–Trost Etherification

A highly stereocontrolled, convergent total synthesis of kendomycin [(?)‐TAN2162], an ansa‐macrocyclic antibiotic, is reported. The key of the strategy is an unprecedented Tsuji–Trost macrocyclic etherification, followed by a transannular Claisen rearrangement to construct the 18‐membered carbocyclic framework. The oxa‐six‐ and five‐membered rings were also stereoselectively constructed respectively by a cascade oxidative cyclization at an unfunctionalized benzylic position and using a one‐pot epoxidation/5‐exo‐tet epoxide opening.     

Cyclization Reactions of Aryl Propargyl Acetates with Tethered Epoxide Induced by Ruthenium Complex

Reactions of the ruthenium complex [Ru]Cl ([Ru]=Cp(PPh₃)₂Ru; Cp=η⁵‐C₅H₅) with several aryl propargyl acetates, each with an ortho ‐substituted chain of various length containing an epoxide on the aromatic ring and with or without methyl substitutents on the epoxide ring, bring about novel cyclizations. The cyclization reactions of HC≡CCH(OAc)(C₆H₄)CH₂(RC₂H₂O) (R=H, 6 a ; R=CH₃, 6 b , where RC₂H₂O is an epoxide ring) in MeOH give the vinylidene complexes 5 a – b , respectively, each with the Cβ integrated into a tetrahydro‐5H ‐benzo[7]annulen‐6‐ol ring. A C−C bond formation takes place between the propargyl acetate and the less substituted carbon of the epoxide ring. Further cyclizations of 5 a – b induced by HBF₄ give the corresponding vinylidene complexes 8 a – b each with a new 8‐oxabicyclo‐[3.2.1]octane ring by removal of a methanol molecule in high yield. For similar aryl propargyl acetates with a shorter epoxide chain, the cyclization gives a mixture of a vinylidene complex with a tetrahydronaphthalen‐1‐ol ring and a carbene complex with a tricyclic indeno‐furan ring. For the cyclization of 18 , with a longer epoxide chain, opening of the epoxide is required to afford the vicinal bromohydrin 22 , then tandem cyclization occurs in one pot. Products are characterized by spectroscopic methods as well as by XRD analysis.     

Endo-oxacyclizations of polyepoxides: biomimetic synthesis of fused polycyclic ethers

Boron trifluoride-etherate promotes the endo-selective oxacyclization of polyepoxides derived from various acyclic terpenoid polyalkenes, including geraniol, farnesol, and geranylgeraniol, providing an efficient and stereoselective synthesis of substituted oxepanes and fused polyoxepanes. The mechanism of the oxacyclization reaction probably involves intramolecular nucleophilic addition of epoxide oxygen to open another epoxide that is activated as an electrophile by the Lewis acid. These oxacyclizations proceed stereospecifically with inversion of configuration upon opening of each epoxide to provide trans-fused polycyclic products. The oxacyclization cascade is terminated by a tethered nucleophile, which may be the carbonyl oxygen of a ketone, ester, or carbonate, or a trisubstituted alkene. The best oxacyclization yields are generally observed with tert-butyl carbonate as the terminating nucleophile, although in some cases the oxacyclization products include formation of tert-butyl ethers as a minor product. The oxacyclization transformations described herein may mimic ring-forming steps in the biosynthesis of trans-syn-trans-fused polycyclic ether marine natural products.     

Catalytic,Cascade Ring‐Opening Benzannulations of 2,3‐Dihydrofuran O,O‐ and N,O‐Acetals

An Al(OTf)₃‐catalyzed intramolecular cascade ring‐opening benzannulation of 2,3‐dihydrofuran O,O‐ and N,O‐acetals is described. The cascade sequence involves the dihydrofuran ring‐opening by acetal hydrolysis, an intramolecular Prins‐type cyclization, and aromatization to generate an array of benzo‐fused (hetero)aromatic systems in up to 95 % yield. This method represents the first example of dihydrofuran acetal usage in benzannulation reactions. The approach provides excellent regiocontrol based on the choice of alkenes used to form the requisite dihydrofuran acetals.     

New Cyclization Route to the Skeletons of Lennoxamine and Chilenine

A new cyclization route, triggered by epoxide opening, has been performed to provide the key intermediates for isoindolobenzapine alkaloids, lennoxamine and chilenine. The epoxide was prepared by the Stille reaction using vinyltributylstannane and the following dioxirane treatment. Cyclization under the treatment of BF₃ · OEt₂ provided an azepine moiety, and the oxidative cyclization toward the known precursor for the alkaloids has been achieved by reaction with a stoichiometric amount of Pd(OAc)₂. This formal synthesis suggests a new route to the alkaloids.     

Total Synthesis of (−)‐Cephalotaxine and (−)‐Homoharringtonine via Furan Oxidation–Transannular Mannich Cyclization

Homoharringtonine and its congener cephalotaxine were synthesized. Oxidative ring‐opening of a furan unveils an amine‐tethered dicarbonyl, which undergoes spontaneous transannular Mannich cyclization. The cascade builds the full cephalotaxine substructure in a single operation in 60 % yield. A Noyori reduction enabled synthesis of the title compounds with excellent enantioselectivity (k_rel=278).     

Reactivity of cyclohexene epoxides toward intramolecular acid-catalyzed cyclizations for the synthesis of naturally occurring cage architectures

This account compiles our results on the reactivity of cyclohexene epoxides toward the synthesis of naturally occurring cage architectures, in particular, the one found in harringtonolide. Bicyclic and branched monocyclic functional triads (hydroxy-epoxy-esters) were synthesized with the aim of undertaking cascade processes toward the formation of lactone and/or cycloether bridges, through a central epoxide opening. This work successfully culminated in the cascade cyclization of the fully oxygenated bridge-structure of harringtonolide, by using a dual Brønsted-Lewis acid complex.     

Stereoselective synthesis of the densely functionalized C1-C9 fragment of amphidinolides C and F

The synthesis of the C1-C9 subunit of amphidinolides C and F is described. Key steps include tandem Sharpless asymmetric dihydroxylation-S_N2 cyclization reaction, Lewis acid-mediated epoxide opening, Wittig reaction, and Wacker oxidation.     

A Novel Route to the Fused Maleic Anhydride Moiety of CP Molecules

A seven‐step cascade reaction —in which selective mesylation, epoxide formation, epoxide lysis, cyclization, reiterative oxidation, and nitrogen–oxygen exchange occur sequentially—facilitates the construction of the maleic anhydride moiety of CP molecules 1 and 2 (>93% yield per step). Unstable intermediates of this reaction sequence were detected, providing evidence for the proposed mechanism and resulting in the discovery of a new chemical entity.     

Synthetic studies on cytotoxic macrolides cruentarens A and B: stereoselective synthesis of the C8–C19 segment of cruentarens A and B

A stereoselective synthesis of the C₈–C₁₉ segment of cruentarens A and B, cytotoxic natural products, has been accomplished. The key steps involve a stereoselective radical cyclization, stereospecific methylation of a γ, δ-epoxy acrylate, nucleophilic epoxide ring opening and a cis-Wittig olefination.     

Synthesis of the cis-fused hexahydroxanthene system via cationic cascade cyclization

The cis-fused hexahydroxanthene system can be obtained through a cascade cyclization initiated by Lewis acid-mediated epoxide opening and terminated by reaction with a MOM-protected phenol. Only a single diastereomer of the product was obtained with stereochemistry verified by diffraction analysis. This demonstrates the viability of this approach to natural products containing the cis-fused hexahydroxanthene skeleton, and supports preparation of more complex targets through a similar strategy.     

Stereoselective synthesis of contiguous THF–THF and THF–THP units via Pd-catalyzed tandem reaction with 1,3-chirality transfer

The Pd^II-catalyzed tandem cyclization of chiral allylic alcohols possessing an internal epoxide and a terminal alcohol provided a contiguous THF–THP and THF–THP ring units stereospecifically. The cyclizations take place via a 5-exo-tet-5-exo-trig mode, however, the cyclization of methyl substituted epoxy diols proceeded via 6-endo-tet-6-exo-trig fashion in a part to construct the oxygen-fused THP–THP ring. The different reaction rates of precursors, which are different stereochemistry at allylic alcohol have been elucidated.     

Synthesis of Both Enantiomers of Flavanone and 2‐Methylchromanone

An efficient enantiospecific synthesis of the (R)‐ and (S)‐enantiomers of flavanone and 2‐methylchromanone is described. The key steps are a C,C‐bond formation by ring opening of a chiral epoxide with a dithiane anion, followed by a Mitsunobu cyclization. The products obtained have high enantiomeric purity.     

Synthesis of chiral iodo-N,O-acetonide aminal scaffolds via an efficient cascade reaction of amino acid-derived epoxides

Novel amino acid-derived iodo-N,O-acetonide aminals were developed as chiral, non-epimerizable scaffolds to facilitate complex molecule synthesis. These scaffolds are readily prepared from commercially available amino acid derivatives in ?6 steps, contain an orthogonally-protected β-hydroxy amine moiety, and feature a directly reactive alkyl-iodide group for facile substitution chemistry. Further, a novel ring opening/cyclization cascade reaction was developed to prepare these compounds efficiently (59-72%) from readily available epoxide derivatives.