Highly stereoselective Brønsted acid catalyzed synthesis of spirooxindole pyrans

A Br?nsted acid-catalyzed Prins-type cyclization sequence to construct spirooxindole pyrans in high yields and excellent diastereoselectivity has been developed. The combination of a β-hydroxy dioxinone fragment and isatin dimethyl acetal generate oxa-spirooxindoles efficiently. These compounds are diversifiable scaffolds that tap into the rich chemistry of dioxinones.     

Facile syntheses of 2,2-dimethyl-6-(2-oxoalkyl)-1,3-dioxin-4-ones and the corresponding 6-substituted 4-hydroxy-2-pyrones

A variety of 2,2-dimethyl-6-(2-oxoalkyl)-1,3-dioxin-4-ones 5a-l and the corresponding 6-substituted 4-hydroxy-2-pyrones 3a-l were prepared in high yields under mild reaction conditions by the reaction of 2,2,6-trimethyl-1,3-dioxin-4-one 4 with 1-acylbenzotriazoles 9 in the presence of LDA followed by thermal cyclization of 5a-l to 3a-l. Synthesis of novel 6-(1-benzoylalkyl)-2,2-dimethyl-1,3-dioxin-4-ones 12a-c was achieved by alkylation of dioxinone 5a and their subsequent cyclization gave 5-alkyl-4-hydroxy-2-pyrones 13a-c.     

Efficient two directional syntheses of a homophthalate ester and novel resorcylate oligomers

Thermolysis of 6,6′-(2-oxopropane-1,3-diyl)bis(2,2-dimethyl-4H-1,3-dioxin-4-one) in the presence of methanol gave a triketo-ester which subsequently aromatized to provide a synthetically useful homophthalate ester. Enolate C-acylation in the presence of diethylzinc was used to synthesize other double diketo-dioxinones, which on cyclization, aromatization and dioxinone ring opening gave novel double resorcylate derivatives.     

Total Synthesis of (−)‐Vindorosine

Outlined herein is a novel and scalable synthesis of (−)‐vindorosine based on two key transformations. A highly diastereoselective vinylogous Mannich addition of dioxinone‐derived lithium dienolates with indolyl N ‐tert‐butanesulfinyl imines has been developed. In addition, an intramolecular Heathcock/aza‐Prins cyclization was introduced to construct both the C, and the highly substituted E rings for the synthesis of (−)‐vindorosine and related alkaloids.     

Biomimetic synthetic studies on lactonamycin: an expedient synthesis of dihydroxy-isoindolinone-carboxylates

The synthesis of dihydroxy-isoindolinone-carboxylates from a dioxinone keto-ester and N-protected sarcosine without the use of phenolic protection is described. Base-induced aromatization of the dioxinone diketo-ester followed by lactamization furnished the desired dihydroxy-isoindolinone moiety, which could be used as an EF-ring precursor toward the synthesis of lactonamycin.     

A hetero-Diels-Alder approach to complex pyrones: an improved synthesis of the spongistatin AB spiroketal

[STRUCTURE: SEE TEXT] The conversion of a substituted dioxinone to a pyrone was used in an improved synthesis of the AB spiroketal subunit of the spongistatins. This transformation occurred via a hetero-Diels-Alder reaction of an acyl ketene with butyl vinyl ether. A double diastereoselective Mukaiyama aldol reaction is used to provide the hetero-Diels-Alder precursor.     

Mechanistic studies of highly regioselective decarboxylative-prenyl migration reactions of prenyloxycarbonyl-diketo-dioxinones

Mechanistic studies of tandem regioselective decarboxylation, prenyl transfer, and aromatization reactions of prenyl dioxinone diketo-carboxylates to provide 3-prenyl-resorcylate derivatives are described. Studies of the effects of concentration and the base employed as well as the results of cross-over experiments were all found to be consistent with the reaction proceeding largely via an intermolecular reaction pathway.     

Synthesis of the C1 to C13 tetrahydropyranyl-resorcylate core of paecilomycin B

A d-Glucose derived tetrahydropyran was converted into the C1 to C13 tetrahydropyranyl-resorcylate core of paecilomycin B in seven steps. Key transformations included the synthesis of a diketo-ester dioxinone, which upon thermolysis underwent a retro-hetero-Diels-Alder fragmentation to generate an acyl ketene. This was subsequently trapped by a secondary alcohol affording a triketo-ester, which was efficiently aromatized to produce the advanced resorcylate intermediate.     

Total synthesis of TAK-kinase inhibitor LL-Z1640-2 via consecutive macrocyclization and transannular aromatization

The biomimetic total synthesis of LL-Z1640-2 (3) is reported without the use of phenol protection. The aromatic unit was constructed via the transannular aromatization of macrocyclic triketo-ester 2, which in turn was synthesized by macrolactonization using an intramolecular trapping of a triketo-ketene derived from dioxinone 1.     

Total Synthesis of Aetheramide A

The first total synthesis of the highly potent anti‐HIV natural product aetheramide A was accomplished in 18 steps from four equally complex building blocks. The synthesis established the unknown configuration at C26 and used a configurationally labile β‐ketoester moiety for the self‐adjustment of the configuration at a methyl branch. The pivotal macrolactamization was achieved by trapping a thermally generated acylketene which was derived from its corresponding dioxinone.     

Cyclization reactions of methylthioacetanilides

The cyclization reactions of methylthioacetanilides mediated by manganese(III) acetate and/or copper(II) acetate are described. Indolinones and indolinediones can be produced effectively via a 5-membered ring cyclization of methylthioacetanilides. The product distributions are highly dependent on the reaction conditions. In most cases, the electronic effect of the substituents on the aryl ring was found to significantly affect the yields of cyclization products. This cyclization reaction proceeded faster with manganese(III) acetate/copper(II) acetate.     

Studies towards a total synthesis of kainic acid

The preparation of the fused bicycle 14 is reported together with its photocyclisation to the dioxinone 2. Base induced fragmentation of the photoadduct 15 formed exclusively in the aforementioned photocylisation, followed by Wittig methylenation gave the kainoid derivative 18.     

Asymmetric Disulfonimide‐Catalyzed Synthesis of δ‐Amino‐β‐Ketoester Derivatives by Vinylogous Mukaiyama–Mannich Reactions

An organocatalytic asymmetric synthesis of δ‐amino‐β‐ketoester derivatives has been developed. A chiral disulfonimide (DSI) serves as a highly efficient precatalyst for a vinylogous Mukaiyama–Mannich reaction of readily available dioxinone‐derived silyloxydienes with N‐Boc‐protected imines, delivering products in excellent yields and enantioselectivities. The synthetic utility of this reaction is illustrated in various transformations, including a new C? C bond‐forming reaction, which provide useful enantioenriched building blocks. The methodology is applied in a formal synthesis of (?)‐lasubin.     

Photochemically induced electron transfer (PET) catalyzed radical cyclization: a practical method for inducing structural changes in peptides by formation of cyclic amino acid derivatives

A new radical cyclization reaction of unsaturated amino acid derivatives is presented. The reaction is induced by photoelectron transfer (PET) catalysis and proceeds, in comparison to commonly applied methods, under mild, nonoxidizing, and nontoxic conditions in neutral medium. This type of radical cyclization reaction can be used in peptide chemistry for inducing structural changes in peptides.     

Synthesis of 6- and 7-membered cyclic enaminones: scope and mechanism

Six- and seven-membered cyclic enaminones can be prepared using common, environmentally benign reagents. Amino acids are used as synthetic precursors allowing diversification and the incorporation of chirality. The key reaction in this multistep process involves deprotection of Boc-amino ynones and subsequent treatment with methanolic K(2)CO(3) to induce cyclization. A β-amino elimination side reaction was identified in a few labile substrates that led to either loss of stereochemical purity or degradation. This process can be mitigated in specific cases using mild deprotection conditions. NMR and deuterium-labeling experiments provided valuable insight into the workings and limitations of this reaction. Although disguised as a 6-endo-dig cyclization, the reagents employed in the transformation play a direct role in bond-making and bond-breaking, thus changing the mode of addition to a 6-endo-trig cyclization. This method can be used to construct an array of monocyclic and bicyclic scaffolds, many of which are found in well-known natural products (e.g., indolizidine, quinolizidine, and Stemona alkaloids).     

The scope and limitations of 1,3-stannyl shift-promoted intramolecular cyclizations of alpha-stannyl radicals with a formyl group

Alpha-tributylstannyl radicals can be generated from the corresponding bromides or xanthates. These radicals undergo efficient intramolecular 1,5-cyclizations with a formyl group. The resulting beta-stannyl alkoxy radicals proceed through a 1,3-stannyl shift from carbon to oxygen to afford beta-stannyloxy radicals. This novel rearrangement is most likely irreversible and serves as a driving force to promote the cyclizations. Although the cyclization rates can be accelerated when the formyl group carries alpha-dimethyl substituents, unfortunately beta-scission of the alkoxy radicals becomes competitive with the 1,3-stannyl shift. The beta-stannyloxy radicals can be employed in further cyclizations to obtain tandem cyclization products.     

Synthesis of tetrahydrofurans by cyclization of homoallylic alcohols with iodine/iodine(III)

Tetrahydrofuran derivatives can be obtained by cyclofunctionalization of homoallylic alcohols bearing a terminal double bound by using [hydroxy(tosyloxy)iodo]benzene (HTIB, Koser's reagent) in the presence of a catalytic amount of I(2) (20 mol %) in MeOH under mild conditions. This transformation is an overall 5-endo-trig cyclization, which occurs by two different pathways. The first is a 4-exo-trig cyclization followed by ring expansion, whereas the second is an electrophilic addition followed by a 5-endo-tet cyclization.     

A single residue switch converts abietadiene synthase into a pimaradiene specific cyclase

Terpene synthases often catalyze complex cyclization reactions that typically represent the committed step in particular biosynthetic pathways, leading to great interest in their enzymatic mechanisms. We have recently demonstrated that substitution of a specific Ile with Thr was sufficient to "short circuit" the complex cyclization reaction normally catalyzed by ent-kaurene synthases to instead produce ent-pimaradiene. Here we report that the complex cyclization/rearrangement reaction catalyzed by abietadiene synthase can be similarly cut short to produce pimaradienes by an analogous Ser for Ala change, albeit with a slight shift in active site location to accommodate the difference in substrate stereochemistry. This result has mechanistic implications for enzymatic catalysis of abietadiene cyclization, and terpene synthases more broadly. Furthermore, these defined single residue switches may be useful in engineering product outcome in diterpene synthases more generally.     

Consecutive carbon-carbon bond formation approach in tandem cyclization reactions

The conventional tandem cyclization reactions involve the formation of alternating carbon-carbon bonds, whereas the newly developed cyclization reactions involve the formation of consecutive carbon-carbon bonds, in which N-aziridinylimines have been utilized as geminal radical acceptor and donor equivalents in a single operation. This unprecedented tandem cyclization approach becomes feasible by the successful generation of 5- and 6-membered ring radicals by radical cyclizations of N-aziridinylimines. The same notion can be applied to the anionic cyclizations of N-aziridinylimines, thereby allowing anionic consecutive carbon-carbon bond formation. This approach has great synthetic potential, particularly for the construction of quaternary carbon centers, and it provides highly efficient routes for the synthesis of natural products.     

Enantiodivergent Cyclization by Inversion of the Reactivity in Ambiphilic Molecules

Inverting the reactivity of the functional groups in ambiphilic molecules provides a new synthetic strategy to perform late‐stage enantiodivergence. Both enantiomers of the final compound can be obtained from a common chiral precursor. As a proof of concept, the synthesis of substituted five‐ and six‐membered oxacycles is described. The key step is the cyclization of an ambiphilic linear precursor bearing a propargylic alcohol and an epoxide linked through an alkyl chain. Through a slight modification of these linear precursors and employing different reaction conditions, these functional groups can inverse their chemical reactivity, producing one enantiomer or another of the final product. This enantiodivergent cyclization involves three stereogenic centers that can undergo fully controlled retention or inversion of their configuration depending on the cyclization pathway that is activated. The cyclization provides late‐stage enantiodivergence, enabling the synthesis of either enantiomers of the oxacycles from a common chiral substrate with total transfer of the enantiomeric purity.