Electrooxidative coupling of furans and silyl enol ethers: application to the synthesis of annulated furans

The preparation of annulated furan systems as key synthetic intermediates through the application of a two-step annulation involving an electrochemical ring closure between a furan and a silyl enol ether has been studied. The reaction was shown to be quite general for the formation of six-membered rings in good yields and was tolerant of a variety of different functional groups. The ring closure was highly stereoselective, leading to the formation of cis-fused systems. Cyclic voltammetry and probe molecules were used to gain mechanistic insight into the reaction. These studies suggested that the key ring closure involved an initial oxidation of the silyl enol ether to a radical cation followed by a furan-terminated cyclization.     

Anodic cyclization reactions: the total synthesis of alliacol a

An anodic cyclization-Friedel Crafts alkylation strategy has been used to rapidly assemble the core ring system of alliacol A and to complete a formal total synthesis of the natural product. The anodic cyclization reaction was used to effect the coupling of a nucleophilic furan ring to the normally nucleophilic carbon of a silyl enol ether. The substrate for this initial cyclization reaction contained all of the carbons needed for completing the total synthesis. The electrolysis proceeded in high yield and could be accomplished with the use of a 6 V lantern battery.     

Convergent, stereoselective synthesis of the GHIJ fragment of brevetoxin A

[reaction: see text] A stereoselective synthesis of the GHIJ fragment of brevetoxin A utilizing a convergent assembly strategy is described. Glycolate alkylation, ring-closing metathesis, and Hosomi-Sakurai reactions were central operations in the construction of the G ring and J ring subunits, which were united through a Horner-Wadsworth-Emmons coupling. Subsequent dehydrative cyclization produced an endocyclic enol ether that was further elaborated to the tetracyclic GHIJ fragment of brevetoxin A.     

Two-step electrochemical annulation for the assembly of polycyclic systems

[reaction: see text] A two-step electrochemical annulation has been developed for the preparation of fused furans. The process involves an initial conjugate addition of a furyethyl cuprate and trapping of the enolate as the corresponding silyl enolether. The second step of the annulation involves the anodic coupling of the furan and the silyl enol ether to form a six-membered ring.     

Oxidative cyclization based on reversing the polarity of enol ethers and ketene dithioacetals. Construction of a tetrahydrofuran ring and application to the synthesis of (+)-nemorensic Acid

The utility of oxidative cyclization reactions for the construction of tetrahydrofuran rings has been examined. In these experiments, alcohol nucleophiles were found to be effective traps for radical cation intermediates generated from both enol ether and ketene dithioacetal groups. The reactivity of the alcohol trapping group appeared to lie between that of an enol ether and an allylsilane trapping group. The stereochemical outcome of cyclization reactions originating from the oxidation of an enol ether was found to be controlled by stereoelectronic factors. The utility of these cyclization reactions was illustrated with the synthesis of a key tetrahydrofuran building block for the synthesis of linalool oxide and rotundisine. Cyclization reactions triggered by the oxidation of a ketene dithioacetal led to far greater levels of stereoselectivity. The stereochemical outcome of these reactions was shown to arise from steric factors involving the larger ketene acetal group. The synthetic utility of cyclizations utilizing ketene dithioacetal derived radical cations was demonstrated by completing an asymmetric synthesis of (+)-nemorensic acid. Finally, the reactions were shown to be compatible with the use of an amide nucleophile and the direct formation of a lactone product.     

Synthesis of a chiral steroid ring D precursor starting from carvone

A chiral five-membered, silyl enol ether containing, steroid ring D precursor has been synthesized from carvone. This silyl enol ether has been applied in the synthesis of a chiral C17 functionalized steroid skeleton using the addition of a carbocation, generated with ZnBr₂ from a Torgov reagent, followed by cyclization of the adduct by treatment with acid.     

New approaches toward the synthesis of (D-homo) steroid skeletons using Mukaiyama reactions

New, short, and flexible procedures have been developed for syntheses of steroid and D-homo steroid skeletons. A Mukaiyama reaction between the silyl enol ether of 6-methoxytetralone and 2-methyl-2-cyclopentenone or carvone, with transfer of the silyl group to the receiving enone, gave a second silyl enol ether. Addition of a carbocation, generated under Lewis acid conditions from 3-methoxy-2-butenol, 3-ethoxy-3-phenyl-2-propenol or 3-methoxy-2-propenol to this second silyl enol ether gave adducts, which could not be cyclized by aldol condensation to (D-homo) steroid skeletons. The Mukaiyama-Michael reaction of the silyl enol ether of 6-methoxy tetralone with 2-methyl-2-cylopentenone gave a second silyl enol ether, which reacted in high yield with a carbocation generated from 3-hydroxy-3-(4-methoxyphenyl)propene. Ozonolysis of the double bond in this adduct gave a tricarbonyl compound (Zieglers triketone), which has been used before in the synthesis of 9,11-dehydroestrone methyl ether. A second synthesis of C17 substituted CD-trans coupled (D-homo) steroid skeletons has been developed via addition of a carbocation, generated with ZnBr₂ from a Torgov reagent, to a silyl enol ether containing ring D precursor. The obtained seco steroids have been cyclized under formation of the 8-14 bond by treatment with acid. The double bonds in one of the cyclized products have been reduced to a C17-substituted all trans steroid skeleton.     

Anodic cyclization reactions: capitalizing on an intramolecular electron transfer to trigger the synthesis of a key tetrahydropyran building block

An anodic cyclization reaction between an enol ether radical cation and an oxygen nucleophile has been used to make a tetrahydropyran building block for the C(10)-C(16) portion of bryostatin. The oxidative cyclization was successful despite the presence of a thioacetal group that has a lower oxidation potential than the enol ether. Experimental evidence suggested that the reaction proceeded through an initial oxidation of the thioacetal followed by an intramolecular electron transfer to form the enol ether radical cation that was subsequently trapped by the oxygen nucleophile. The formation of the desired cyclic product could be explained using the Curtin-Hammett principle. By taking advantage of the intramolecular electron-transfer reaction, we used the presence of a thioacetal in an electrolysis substrate to selectively oxidize a proximal enol ether in the presence of an otherwise identical but more remote enol ether.     

Synthetic studies on taxanes: construction of the tricyclic skeleton on the basis of a [6+2] cycloaddition reaction

The stereoselective synthesis of a tricyclic model compound of taxane diterpenes was achieved. The eight-membered B ring was constructed on the basis of a [6+2] cycloaddition reaction of a dicobalt acetylene complex with an enol silyl ether of cyclohexanone. After conversion of the cobalt complex moiety to an epoxide and introduction of a 3-cyanopropyl group, the A ring was formed via an intramolecular cyclization reaction under basic conditions.     

呋喃甲基缩水甘油醚/二氧化碳共聚物的Diels-Alder反应

利用呋喃环侧基与单烯化合物所发生的Diels-Alder( DA)环加成反应,大幅度降低呋喃环在共聚物中的含量,从而制备出空气氛下稳定性较好的二氧化碳共聚物.研究发现DA反应的环加成程度越高,呋喃甲基缩水甘油醚/二氧化碳共聚物(PFGEC)的空气稳定性越好,当环加成程度超过70％时,可以得到稳定产物.DA反应条件对环加...     

Synthesis of polyprenylated acylphloroglucinols using bridgehead lithiation: the total synthesis of racemic clusianone and a formal synthesis of racemic garsubellin A

The synthesis of polyprenylated phloroglucinol natural products, including clusianone, nemorosone, and garsubellin A, was pursued by a strategy involving construction of a core bicyclo[3.3.1]nonanetrione structure and subsequent elaboration via organolithium intermediates. Appropriate bridged core structures were obtained through the cyclization of a suitably substituted cyclohexanone enol ether or enol silane with malonyl dichloride. Additional substituents were then introduced by means of regioselective lithiation reactions, including the generation of bridgehead enolates, thus enabling the total synthesis of clusianone and also of an advanced intermediate toward nemorosone. In the case of garsubellin A, an additional THF-like ring was elaborated by a biomimetic 5-exo-tet cyclization of an enol ether (or enol) with a side-chain epoxide. This enabled a formal synthesis of racemic garsubellin A by accessing one of the late intermediates in the Danishefsky synthesis.     

A catalytic antibody against a tocopherol cyclase inhibitor

The cyclic ammonium cation 5 and its guanidinium analogue 4 are inhibitors of tocopherol cyclase. Monoclonal antibodies were raised against protein conjugates of the haptens 1-3 and screened for catalytic reactions with alkene 8, a short chain analogue of the natural substrate phytyl-hydroquinone 6, and its enol ether analogues 10a,b. Antibody 16E7 raised against hapten 3 was found to catalyze the hydrolysis of Z enol ether 10a to form hemiacetal 12 with an apparent rate acceleration of k(cat)/k(uncat)=1400. Antibody 16E7 also catalyzed the elimination of Kemp's benzisoxazole 59. The absence of cyclization in the reaction of enol ether 10a was attributed to the competition of water molecules for the oxocarbonium cation intermediate within the antibody binding pocket. Hapten and reaction design features contributing to this outcome are discussed. Antibody 16E7 provides the first example of a carboxyl group acting both as an acid in an intrinsically acid-catalyzed process and as a base in an intrinsically base-catalyzed process, as expected from first principles. In contrast to the many examples of general-acid-catalyzed processes known to be catalyzed by catalytic antibodies, the specific-acid-catalyzed cyclization of phytyl-hydroquinone 6 or its analogue 8 still eludes antibody catalysis.     

Synthetic studies of GKK1032s: the asymmetric synthesis of the decahydrofluorene skeleton via a novel cyclization of silyl enol ether and sequential retro Diels-Alder and intramolecular Diels-Alder reactions

GKK1032s, which were isolated from the culture broth of Penicillium sp. GKK1032, exhibit antitumor activity. We constructed the fully elaborated decahydrofluorene skeleton of GKK1032s. The C-ring was constructed by intramolecular cyclization reaction between a chiral epoxide and silyl enol ether, and the dienophile moiety was introduced concurrently. In addition, the AB-rings were stereoselectively constructed using novel sequential retro Diels-Alder (DA) and intramolecular Diels-Alder (IMDA) reactions. Several further modifications of the IMDA adduct were carried out, leading to the asymmetric synthesis of the desired hydroxyester including nine stereo centers.     

Synthesis of cyclobutanones and four-membered enol ethers by using a rearrangement reaction of enol triflates

A new synthetic method of cyclobutanone derivatives and four-membered enol ethers via an intramolecular cyclization of a ketone enolate was developed. The cyclization precursors, enol triflates having a silyloxy group at the β′-position, were synthesized from the corresponding β-hydroxy ketones, which were prepared via an aldol reaction of a cycloalkanone and an aldehyde. Under the influence of TBAF, the enol triflates afforded a cyclobutanone or a four-membered enol ether through rearrangement of the trifluoromethanesulfonyl group followed by an intramolecular C- or O-alkylation reaction.     

A study of vinyl radical cyclization using N-alkenyl-7-bromo-substituted hexahydroindolinones

A new method for the synthesis of the octahydropyrrolo[3,2,1-ij]quinoline ring system that possesses the characteristic skeleton of the aspidosperma family of alkaloids has been developed. The method utilizes an intramolecular Diels-Alder reaction of an amido-substituted furan across a tethered indole pi-bond. To apply this strategy to the synthesis of the indole alkaloid spegazzinidine, it was necessary to address the problem of assembling the final D-ring of the pentacyclic skeleton. Radical cyclization of a model N-allyl-7-bromo-3a-methylhexahydroindolinone system was found to preferentially lead to the 6-endo-trig cyclization product, with the best yield being obtained under high dilution conditions. The six-membered cyclized product is generated through two reaction pathways: (a) 6-endo-trig ring closure and (b) rearrangement of an intermediate methylene-cyclopentyl radical obtained by 5-exo-trig cyclization. A number of related 7-bromo-substituted hexahydroindolinones containing tethered olefinic groups were prepared and found to undergo efficient cyclization under both radical and palladium-mediated reaction conditions. Vinyl radical cyclization with several N-butenyl-substituted systems afforded a mixture of 6-exo and 7-endo cyclization products. A protocol to introduce an ethyl substituent into the C20-position of the aspidospermidine skeleton was also developed.     

Intramolecular Anodic Olefin Coupling Reactions and the Use of Electron-Rich Aryl Rings(1)

The utility of intramolecular anodic olefin coupling reactions involving electron-rich aromatic rings for constructing fused, bicyclic ring skeletons has been examined. Reactions involving alkoxy-substituted phenyl rings were found to benefit strongly from a 3-methoxy substituent on the phenyl ring. Although overoxidation of the bicyclic product was observed in these reactions, this problem could be minimized with the use of controlled potential electrolysis conditions when a monomethoxy phenyl ring was used and avoided entirely with the use of a vinyl sulfide moiety as the initiator when a more electron-rich phenyl ring was used. Reactions involving 4-alkoxy-substituted phenyl rings as substrates did not lead to good yields of fused products. Furan rings were found to be excellent coupling partners for the reactions and afforded products having fused, bicyclic furan ring skeletons. Cyclizations involving furans were shown to be compatible with the formation of both six- and seven-membered rings, the generation of a quaternary carbon, and the use of a variety of electron-rich olefins as the other coupling partner. It appears that the furan can serve as either the initiating group or the terminating group for the cyclizations. Finally, the reactions were shown to be compatible with the use of a pyrrole ring as one of the participants.     

Acid-promoted cyclization reactions of tetrahydroindolinones. Model studies for possible application in a synthesis of selaginoidine

The synthesis of various substituted bicyclic lactams by an acid-induced Pictet-Spengler reaction of tetrahydroindolinones bearing tethered heteroaromatic rings is presented. The outcome of the cyclization depends on the position of the furan tether, tether length, nature of the tethered heteroaromatic ring, and the substituent group present on the 5-position of the tethered heteroaryl group. A one-pot procedure was developed to efficiently prepare tetrahydroindolinones containing tethered furan rings. In a typical example, the reaction of furanyl azide 26 with n-Bu3P delivered iminophosphorane 27, which was allowed to react with a 1-alkyl-(2-oxocyclohexyl)acetic acid to provide the desired furanyl-substituted tetrahydroindolinone system 29. Treatment of 29 with trifluoroacetic acid afforded the tetracyclic lactam skeleton 30 found in the alkaloid (+/-)-selaginoidine.     

Enantioselective Total Synthesis of Cymoside through a Bioinspired Oxidative Cyclization of a Strictosidine Derivative

The first total synthesis of the caged monoterpene indole alkaloid cymoside is reported. This natural product displays a unique hexacyclic‐fused skeleton whose biosynthesis implies an early oxidative cyclization of strictosidine. Our approach to the furo[3,2‐b]indoline framework relied on an unprecedented biomimetic sequence which started by the diastereoselective oxidation of the indole ring into a hydroxyindolenine which triggered the addition of an enol ether and was followed by the trapping of an oxocarbenium intermediate.     

Domino Mukaiyama-Michael reactions in the synthesis of polycyclic systems

Good results were obtained in the Mukaiyama-Michael reaction of the silyl enol ether of cyclohexanone with 2-methyl-2-cyclopentenone and carvone, with transfer of the silyl group to the receiving enone and with TrSbCl₆ as catalyst. A second Mukaiyama-Michael reaction of this new silyl enol ether with methyl vinyl ketone and cyclization of the resulting adduct leads to tricyclic compounds in one-pot domino sequences. The scope and limitations of this domino reaction have been investigated.     

A concise synthesis of the functionalized [5-7-6] tricyclic skeleton of guanacastepene A

The six membered ring of guanacastepene A was constructed by a Diels-Alder reaction of 1,1,4-trisubstituted diene to set up the correct relative stereochemistry at the C8 quaternary center and the remote C5 stereocenter. In 10 efficient steps from the Diels-Alder adduct 9, the desired highly functionalized [5-7-6] tricyclic skeleton 2 was synthesized. Key steps involve trimethylsilyl chloride (TMSCl) assisted Michael addition to form enol ether and the usage of the enol ether in the following intramolecular Mukaiyama aldol reaction to form the middle seven membered ring of guanacastepene A.