Anodic cyclization reactions: reversing the polarity of ketene dithioacetal groups

Intramolecular coupling reactions of ketene dithioacetal groups with enol ether and alcohol nucleophiles have been studied. The reactions were initiated by an anodic oxidation of the ketene dithioacetal and proved to be compatible with the formation of five- or six-member rings, as well as the stereoselective generation of quaternary carbons.     

Oxidative cyclization reactions: amide trapping groups and the synthesis of furanones

Intramolecular anodic coupling reactions involving ketene dithioacetal radical cations and amide trapping groups have been examined. The reactions generate furanone products and benefit greatly from the addition of water to the reaction medium. The cyclization reactions lead to products having stereochemistry that is directly analogous to oxidative cyclization reactions utilizing ketene dithioiacetal radical cations and alcohol trapping groups. [reaction: see text]     

Anodic cyclization reactions: probing the chemistry of N,O-ketene acetal derived radical cations

The chemical reactivity of radical cations derived from N,O-ketene acetals has been examined and compared with the reactivity of radical cations derived from both ketene dithioacetals and enol ethers. Synthetically, the N,O-ketene acetal radical cations lead to more efficient cyclization reactions than either the ketene dithioacetal or enol ether derived radical cations. Cyclic voltammetry experiments using allylsilane trapping groups show that the efficiency of these cyclizations is not due to the N,O-ketene acetal radical cations being more reactive but rather more stable to decomposition. Finally, cyclizations using chiral oxizolidinones were examined.     

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.     

Anodic cyclization reactions and the synthesis of (−)-crobarbatic acid

A synthesis of (−)-crobarbatic acid is reported along with the first use of a vinyl-substituted ketene dithioacetal as a coupling partner for an anodic cyclization reaction. The use of the vinyl-substituted ketene dithioacetal enables the construction of a cyclic product having a tetrasubstituted carbon with a relative stereochemistry opposite to that originally obtained from the cyclization.     

Chemoselective oxygen-centered radical cyclizations onto silyl enol ethers

A new oxygen-centered radical cyclization onto silyl enol ethers has been developed and utilized for the synthesis of versatile siloxy-substituted tetrahydrofurans. The reactions display excellent chemoselectivity for cyclization onto the electron-rich silyl enol ether when competing terminal alkene cyclization, 1,5-hydrogen abstraction, and beta-fragmentation pathways are present. The increased chemoselectivity also allows for the synthesis of tetrahydropyrans, a challenging substrate class to access using oxygen-centered radical alkene cyclizations due to competing 1,5-hydrogen abstractions.     

Trimethyl Orthoacetate and Ethylene Glycol Mono‐Vinyl Ether as Enolate Surrogates in Enantioselective Iridium‐Catalyzed Allylation

Trimethyl orthoacetate and ethylene glycol mono‐vinyl ether are employed in iridium‐catalyzed enantioselective allylation reactions. The method documented enables their convenient use as surrogates for silyl ketene acetals and silyl enol ethers to prepare γ,δ‐unsaturated esters and protected aldehydes with excellent enantioselectivity. The utility of this novel method has been demonstrated by its implementation in a formal enantioselective synthesis of the meroterpenoid (+)‐conicol.     

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.     

Alkoxy radical cyclizations onto silyl enol ethers relative to alkene cyclization, hydrogen atom transfer, and fragmentation reactions

This study examines the chemoselectivity of alkoxy radical cyclizations onto silyl enol ethers compared to competing cyclizations, 1,5-hydrogen atom transfers (1,5-HATs), and β-fragmentations. Cyclization onto silyl enol ethers in a 5-exo mode is greatly preferred over cyclization onto a terminal alkene. The selectivity decreases when any alkyl substitution is present on the competing alkene radical acceptor. Alkoxy radical 5-exo cyclizations displayed excellent chemoselectivity over competing β-fragmentations. Alkoxy radical 5-exo cyclizations onto silyl enol ether also outcompeted 1,5-HATs, even for activated benzylic hydrogen atoms. In tetrahydropyran synthesis, where 1,5-HAT has plagued alkoxy radical cyclization methodologies, 6-exo cyclizations were the dominant mode of reactivity. β-Fragmentation still remains a challenge for tetrahydropyran synthesis when an aryl group is present in the β position.     

Anodic coupling reactions: probing the stereochemistry of tetrahydrofuran formation. A short, convenient synthesis of linalool oxide

[reaction: see text]. Intramolecular coupling reactions between enol ether radical cations and oxygen nucleophiles are primarily governed by stereoelectronics. By taking advantage of this observation, a tetrahydrofuran building block for use in constructing (+)-linalool oxide and rotundisine has been synthesized in four steps from a commercially available starting material. The synthesis of (+)-linalool oxide has been completed.     

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.     

Laser flash photolysis kinetic studies of enol ether radical cations. Rate constants for heterolysis of alpha-methoxy-beta-phosphatoxyalkyl radicals and for cyclizations of enol ether radical cations

Two series of enol ether radical cations were studied by laser flash photolysis methods. The radical cations were produced by heterolyses of the phosphate groups from the corresponding alpha-methoxy-beta-diethylphosphatoxy or beta-diphenylphosphatoxy radicals that were produced by 355 nm photolysis of N-hydroxypryidine-2-thione (PTOC) ester radical precursors. Syntheses of the radical precursors are described. Cyclizations of enol ether radical cations 1 gave distonic radical cations containing the diphenylalkyl radical, whereas cyclizations of enol ether radical cations 2 gave distonic radical cation products containing a diphenylcyclopropylcarbinyl radical moiety that rapidly ring-opened to a diphenylalkyl radical product. For 5-exo cyclizations, the heterolysis reactions were rate limiting, whereas for 6-exo and 7-exo cyclizations, the heterolyses were fast and the cyclizations were rate limiting. Rate constants were measured in acetonitrile and in acetonitrile solutions containing 2,2,2-trifluoroethanol, and several Arrhenius functions were determined. The heterolysis reactions showed a strong solvent polarity effect, whereas the cyclization reactions that gave distonic radical cation products did not. Recombination reactions or deprotonations of the radical cation within the first-formed ion pair compete with diffusive escape of the ions, and the yields of distonic radical cation products were a function of solvent polarity and increased in more polar solvent mixtures. The 5-exo cyclizations were fast enough to compete efficiently with other reactions within the ion pair (k approximately 2 x 10(9) s(-1) at 20 degrees C). The 6-exo cyclization reactions of the enol ether radical cations are 100 times faster (radical cations 1) and 10 000 times faster (radical cations 2) than cyclizations of the corresponding radicals (k approximately 4 x 10(7) s(-1) at 20 degrees C). Second-order rate constants were determined for reactions of one enol ether radical cation with water and with methanol; the rate constants at ambient temperature are 1.1 x 10(6) and 1.4 x 10(6) M(-1) s(-1), respectively.     

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.     

Acyclic stereoselection in the reaction of nucleophilic reagents with chiral N-acyliminium ions generated from N-

Optically active N-[1-(phenylsulfonyl)alkyl]imidazolidin-2-ones react at low temperature in the presence of tin tetrachloride to give acyclic N-acyliminium ions. These electrophilic substrates give addition products upon reaction with pi-nucleophiles. Allyltrimethylsilane affords the corresponding allylated products in good yields and high diastereoselectivity. The stereochemical outcome of this process can be rationalized by taking into account the preference of the intermediate N-acyliminium ion for an E configuration that favors the attack of the nucleophile from the si-si face. Disappointing results are obtained using silyl ketene acetals; conversely trimethylsilyl enol ether of acetophenone gives the corresponding adducts in high diastereoselectivity. The utilization of trimethylsilyl enol ether of 2-acetylfuran is particularly interesting since the corresponding adducts are obtained with good diastereoselectivity and the furan ring could be amenable of further synthetic transformations.     

Intramolecular regioselective addition of radicals and carbanions to ynol ethers. A strategy for the synthesis of exocyclic enol ethers

The scope and limitations of radical and anionic cyclization reactions involving halo ynol ethers have been investigated. 5-exo and 6-exo radical cyclizations of 6-iodo and 7-iodo ynol ethers proceeded well when the oxygen of the ynol ether was bearing an ethyl group. Exocyclic iodoenol ethers resulting from these cyclizations were highly unstable and decomposed rapidly. Li-I exchange of iodo ynol ethers proceeded smoothly at −78 °C. 6-Alkoxy-5-hexynyllithiums underwent regiospecific 5-exo-dig anionic cyclization to produce five-membered rings bearing an exocyclic enol ether moiety. The cyclized vinyllithium intermediate was successfully trapped with electrophiles to afford functionalized cycloalkoxyalkylidene derivatives in modest to good yields. 7-Alkoxy-6-heptynyllithiums did not cyclize via a 6-exo anionic process.     

Mechanistic studies on a sulfoxide transfer reaction mediated by diphenyl sulfoxide/triflic anhydride

Sulfoxides are frequently used in organic synthesis as chiral auxiliaries and reagents to mediate a wide variety of chemical transformations. For example, diphenyl sulfoxide and triflic anhydride can be used to activate a wide range of glycosyl donors including hemiacetals, glycals and thioglycosides. In this way, an alcohol, enol or sulfide is converted into a good leaving group for subsequent reaction with an acceptor alcohol. However, reaction of diphenyl sulfoxide and triflic anhydride with oxathiane-based thioglycosides, and other oxathianes, leads to a different process in which the thioglycoside is oxidised to a sulfoxide. This unexpected oxidation reaction is very stereoselective and proceeds under anhydrous conditions in which the diphenyl sulfoxide acts both as oxidant and as the source of the oxygen atom. Isotopic labelling experiments support a reaction mechanism that involves the formation of oxodisulfonium (S-O-S) dication intermediates. These intermediates undergo oxygen-exchange reactions with other sulfoxides and also allow interconversion of axial and equatorial sulfoxides in oxathiane rings. The reversibility of the oxygen-exchange reaction suggests that the stereochemical outcome of the oxidation reaction may be under thermodynamic control, which potentially presents a novel strategy for the stereoselective synthesis of sulfoxides.     

Preparation of alpha-(2,2-diphenylhydrazino)lactones and related compounds by radical cyclization: use of glyoxylic acid hydrazone derivatives

Glyoxylic acid diphenylhydrazone (2a) and the corresponding O-benzyloxime (2b) are easily esterified in high yield by beta-bromo alcohols. The resulting esters undergo radical cyclization to alpha-(2,2-diphenylhydrazino)- or alpha-[(phenylmethoxy)amino]lactones on treatment with tributyltin hydride. Esters for radical cyclization were also made using a beta-(phenylseleno) alcohol and an enol ether. Several derivatives of glyoxylic acid were evaluated, but none was as effective as 2a or 2b. The imine 28 was prepared by an indirect route; it undergoes radical cyclization with displacement of the nitrogen substituent (28 --> 30) so that an alpha-amino lactone can be generated by acid hydrolysis of the cyclization product.     

Anodic coupling reactions: a sequential cyclization route to the arteannuin ring skeleton

A pair of intramolecular anodic olefin coupling reactions has been used to construct the arteannuin ring skeleton. Both coupling reactions took advantage of a furan ring as one of the coupling partners. In the first, it was found that an enol ether derived from an aldehyde was not an effective initiating group for the reaction. Instead, the cyclization benefited strongly from the use of a N,O-ketene acetal initiating group. In the second cyclization, an endocyclic enol ether was coupled to the furan ring. This second electrolysis reaction generated the key tetrasubstituted carbon at the center of the arteannuin ring skeleton.     

Radical reactions of epoxy esters induced by titanocene chloride

The reductive radical cyclizations of several epoxy esters have been achieved using titanocene chloride. The tether length from the initial radical to the carbonyl acceptor is the key of the reactions. We obtained products from radical cyclization onto carbonyl formate and products from formate and hydrogen elimination. The stereochemical outcome of the 5-exo radical cyclization of two diastereomers is reported. A radical cascade cyclization of an unsaturated epoxy formate is also described.     

Total Synthesis of (+)‐Asteriscanolide: Further Exploration of the Rhodium(I)‐Catalyzed [(5+2)+1] Reaction of Ene‐Vinylcyclopropanes and CO

The total synthesis of (+)‐asteriscanolide is reported. The synthetic route features two key reactions: 1) the rhodium(I)‐catalyzed [(5+2)+1] cycloaddition of a chiral ene‐vinylcyclopropane (ene‐VCP) substrate to construct the [6.3.0] carbocyclic core with excellent asymmetric induction, and 2) an alkoxycarbonyl‐radical cyclization that builds the bridging butyrolactone ring with high efficiency. Other features of this synthetic route include the catalytic asymmetric alkynylation of an aldehyde to synthesize the chiral ene‐VCP substrate, a highly regioselective conversion of the [(5+2)+1] cycloadduct into its enol triflate, and the inversion of the inside–outside tricycle to the outside–outside structure by an ester‐reduction/elimination to enol‐ether/hydrogenation procedure. In addition, density functional theory (DFT) rationalization of the chiral induction of the [(5+2)+1] reaction and the diastereoselectivity of the radical annulation has been presented. Equally important is that we have also developed other routes to synthesize asteriscanolide using the rhodium(I)‐catalyzed [(5+2)+1] cycloaddition as the key step. Even though these routes failed to achieve the total synthesis, these experiments gave further useful information about the scope of the [(5+2)+1] reaction and paved the way for its future application in synthesis.