Sulfonyl-stabilized oxiranyllithium-based approach to polycyclic ethers. Convergent synthesis of the ABCDEF-ring system of yessotoxin and adriatoxin

Convergent synthesis of the ABCDEF-ring system of yessotoxin and adriatoxin, marine polycyclic ether toxins causative of diarrheic shellfish poisoning, has been accomplished. The A-ring fragment was constructed by coupling of an appropriately functionalized sulfonyl-stabilized oxiranyl anion and a triflate prepared from an erythritol derivative. An iterative protocol of the oxiranyl anion strategy was also applied for the construction of the DEF-ring fragment. The triflate derivatives of the A-ring and the DEF-ring fragments were connected with lithium acetylide. The resulting acetylene derivative was further transformed into the hexacyclic ABCDEF fragment via oxidation of the acetylene unit to 1,2-diketone, double methyl acetal formation, and reductive etherification.     

Synthesis of the ABCD ring of gambierol

A fully functionalized ABCD ring moiety of gambierol, a marine polycyclic ether toxin, was synthesized by the use of the oxiranyl anion strategy and reductive cycloetherification of a beta,delta-dihydroxy ketone.     

Total Synthesis of Gambierol by Using Oxiranyl Anions

Gambierol was isolated as a neurotoxin from the cultured cells of the ciguatera causative dinoflagellate Gambierdiscus toxicus and classified as a member of the polycyclic ether family of marine toxins. The structure consists of a ladder‐shaped trans‐fused octacyclic ring system that includes 18 stereogenic centers, two 1,3‐diaxial dimethyl‐substituted tetrahydropyranyl rings, and a partially conjugated triene side chain. The total synthesis of gambierol has been achieved by utilizing an oxiranyl anion strategy in an iterative manner. Synthetic highlights of this route include direct carbon–carbon formation on epoxides, sulfonyl‐assisted 6‐endo cyclization, and an expansion reaction of the tetrahydropyranyl rings to oxepanes to forge the polycyclic architecture of the target molecule.     

Generation and reactions of novel oxiranyl ‘Remote’ anions

Deprotonation of an oxiranyl β-proton takes place in a stereoselective manner providing the corresponding oxiranyl ‘remote’ anion. The anion is stabilized by chelation between the lithium and the carbonyl moiety of an ester, lactone, imide, or keto-group in the form of a five-membered cyclic intermediate. Certain ester-stabilized oxiranyl anions are stable and can be left in THF solution at −78°C for several hours. The generated anions undergo a stereoselective alkylation reaction to provide products, which could be useful intermediates in the synthesis of bioactive naturally occurring α-methylene bis-γ-butyrolactones.     

Base-induced heterochiral dimerization of an oxiranyl carbaldimine: stereoselective synthesis of a highly functionalized aziridine

[reaction: see text] Treatment of the oxiranyl carbaldimine with base (LDA or LDA/KOtBu) leads in an one-step procedure to the polyfunctionalized aziridine. This highly diastereoselective reaction is explained by a new type of an Aza-Darzens reaction, in which one enantiomer of the starting material is deprotonated to form an oxiranyl anion, which attacks the imine carbon atom of the other enantiomer (mutual kinetic resolution by double diastereofacial selection).     

Synthetic study of gymnocin-A: synthesis of the ABC ring fragment

The synthesis of the ABC ring fragment of gymnocin-A is described. The key feature of this approach was the convergent BC ring formation using an oxiranyl anion coupling, which was followed by intramolecular Williamson ether synthesis and the reductive etherification of an α-acetoxy acetal. The five-membered A ring was then constructed on the seven-membered B ring by radical cyclization of a β-alkoxy acrylate derivative.     

A convergent total synthesis of epolactaene: an application of the bridgehead oxiranyl anion strategy

The generation and reaction of a lactone-derived oxiranyl anion is described. The aldol-type reaction of the epoxylactone and aldehydes was accomplished by a two-step procedure via the trimethylsilyl epoxylactone. The application of this methodology to the total synthesis of (+)-epolactaene and its analogs is described.     

Synthesis of the ABCD fragment of gymnocin-B

A convergent synthesis of the ABCD fragment of gymnocin-B was accomplished. The tetracyclic ether ring system was synthesized by the construction of the BC ring system via the oxiranyl anion alkylation and ring expansion reaction, followed by the formation of the five-membered A-ring via a stereoselective radical cyclization reaction of a neopentyl-type iodide.     

Synthesis of trans-fused polycyclic ethers with angular methyl groups using sulfonyl-stabilized oxiranyl anions

An efficient method has been developed for the synthesis of trans-fused tetrahydropyrans with angular methyl groups adjacent to the ring oxygen. The procedure involves the coupling reaction of a sulfonyl-stabilized oxiranyl anion with an appropriate triflate followed by 6-endo cyclization, and is effective for the construction of 6/6- and 6/7/6-cyclic ether ring systems with sterically congested 1,3-diaxial methyl groups.     

Iterative synthesis of the ABCDEF-ring system of yessotoxin and adriatoxin

A stereocontrolled linear synthesis of the ABCDEF-ring system of yessotoxin and adriatoxin, diarrhetic shellfish toxins, is described. Iterative application of a tetrahydropyran synthesis by reaction of the alkylation of a sulfonyl-stabilized oxiranyl anion followed by 6-endo cyclization of a 4,5-epoxy alcohol led to the synthesis of the trans-fused hexacyclic ether system, and the seven-membered E ring was constructed by ring expansion reaction.     

A new stereoselective synthesis of ciguatoxin right wing fragments

The right wings (13 and 14) of ciguatoxins were synthesized highly stereoselectively. Key transformations in the synthesis are (i) an oxiranyl anion strategy to attach the H ring, (ii) intramolecular carbonyl olefination to cyclize the J ring, (iii) regio- and stereoselective reduction of the epoxyacetal to install the C42-stereocenter, and (iv) stereoselective reductive etherification to construct the K ring. The present procedure greatly improved the stereoselectivity and efficiency in comparison to a previous synthesis. Remarkably, only 23 steps were required from monocyclic I ring 5 to construct the ciguatoxin right wings. The high practicality of the present synthesis ensures a sufficient supply of these complex fragments for total syntheses and biomedical applications.     

Trifluoromethyl-stabilized optically active oxiranyl and aziridinyl anions for stereospecific syntheses of trifluoromethylated compounds

Optically active 2,3-epoxy-1,1,1-trifluoropropane was converted into the corresponding oxiranyl anion and reacted with electrophiles such as aldehydes, ketones and halides to give the corresponding adducts in moderate to good yields. The whole reaction occurred with retention of configuration at the stereogenic carbon center. In a similar manner, trifluoromethyl stabilizing aziridinyl anions were generated from the optically active N-tosyl and N-anisyl-2-trifluoromethylaziridines. They also reacted well with various electrophiles. The products of these reactions are versatile synthetic intermediates useful for the synthesis of a variety of trifluoromethylated compounds with quaternary chiral carbon centers.     

Total Synthesis of Epicolactone

The biologically active and structurally complex secondary metabolite epicolactone is a member of the natural product pool found in cash crop endophytes of the genus Epicoccum. By exploiting inherent reactivity, a total synthesis of this highly oxygenated and polycyclic molecule met chemo‐ and regioselectivity challenges. The key buildup of complexity was accomplished via an intramolecular [2+2] photocycloaddition between a quinone and an electron‐deficient diene followed by a cyclobutane ring expansion. The use of a dioxene as an acyl anion equivalent and an intramolecular carbonyl methenylation furnished the natural product.     

Retention of stereochemistry in gold-catalyzed formal [4+3] cycloaddition of epoxides with arenynamides

Golden opportunity: [4+3] Cycloaddition reactions of arenynamides and epoxides are enabled under gold catalysis and have a broad substrate scope (see scheme; Ms=methanesulfonyl). An S(N) 2-type front-side attack of phenyl at the oxiranyl ring is expected to cause the retention of stereochemistry.     

Diastereoselective one-step synthesis of functionalized cis-aziridinyl alcohols from oxiranyl carbaldimines

[reaction: see text]. Upon treatment with lithiumorganic nucleophiles, trans-configured oxiranyl carbaldimines are transformed into anti-configured cis-aziridinyl alcohols with excellent diastereoselectivity. This conversion may be explained by a new type of the aza-Payne rearrangement, including first a nucleophilic attack on the imine carbon atom with diastereofacial differentiation followed by an intramolecular nucleophilic opening of the oxiranyl ring with simultaneous formation of the aziridine ring.     

Unexpected C-C bond cleavage of epoxide motif: rhodium(I)-catalyzed tandem heterocyclization/[4+1] cycloaddition of 1-(1-alkynyl)oxiranyl ketones

A rhodium(I)-catalyzed tandem heterocyclization and formal [4+1] cycloaddition of 1-(1-alkynyl)oxiranyl ketones was developed, which provides a general, efficient and practical route to highly substituted furo[3,4-b]furan-3(2H)-ones, wherein the epoxide motif undergo unexpected C-C bond cleavage rather than the classical C-O bond cleavage.     

A concise route to the right wing of ciguatoxin

A concise route to the HIJKLM-ring fragment 10 of ciguatoxin (CTX) and 51-hydroxyCTX3C was developed in which oxiranyl anion addition and intramolecular carbonyl olefination were utilized as key transformations. The present procedure requires only 23 steps from the I-ring 5, while 35 steps were employed in a previous synthesis of the corresponding right wing 11 of CTX3C. The high efficiency of the present synthesis ensures a supply of 10 for total synthesis and biomedical applications.     

Epoxide formation by ring closure of the cinnamyloxy radical

[formula: see text] The cinnamyloxy and oxiranyl benzyl radicals were generated by photolysis of alkyl 4-nitrobenzenesulfenates. The yet unprecedented epoxide ring formation from a primary alkoxy radical was observed. Experimental evidence supports the fact that the mode of ring opening of the oxiranyl carbinyl radical system is thermodynamically driven. B3LYP/6-31G* calculations indicate that the closed form of the radical is approximately 5 kcal/mol more stable than the open one.     

Polycyclic fused phenanthridines: An alternative approach from benzotriazoles

We describe an alternative approach to polycyclic phenanthridines (7) and some of their analogues using conditions much milder than those previously reported. The procedure includes the generation of a benzotriazole stabilized carbanion, oxidation of the resulting anion to a radical, and elimination of nitrogen followed by ring closure to produce phenanthridines.     

Une etude de la conjugaison entre un systeme aromatique et un cycle a trois chainons

Electron delocalization between a three membered ring (aziridinyl, cyclopropyl, oxiranyl) and an aromatic group was revealed by magnetic rotatory polarization. This conjugation varies according to the relative conformations of these two groups.