The Analysis of Two Distinct Strategies toward the Enantioselective Formal Total Synthesis of (+)-Gelsenicine.

A full account of a formal enantioselective total synthesis of (+)-gelsenicine is described. Separate strategies based on catalytic cycloisomerization as the central step are considered. One plan involves chirality transfer from enantioenriched substrates, while the other employs asymmetric catalysis. The chirality transfer strategy is less effective, while in the latter, phosphoramidite- and bisphosphine-gold complexes are tested and ultimately provide a key intermediate in high enantiopurity in our Gelsemium alkaloid syntheses.

Dearomative (3+2) Cycloadditions between Indoles and Vinyldiazo Species Enabled by a Red-Shifted Chromium Photocatalyst.

A direct dearomative photocatalyzed (3+2) cycloaddition between indoles and vinyldiazo reagents is described. The transformation is enabled by the development of a novel oxidizing CrIII photocatalyst, its specific reactivity attributed to increased absorptive properties over earlier Cr analogs and greater stability than Ru counterparts. A variety of fused indoline compounds are synthesized using this method, including densely functionalized ring systems that are feasible due to base-free conditions. Experimental insights corroborate a cycloaddition initiated by nucleophilic attack at C3 of the indole radical cation by the vinyldiazo species.

Multigram Synthesis of a Combustion-Relevant δ-Ketohydroperoxide through Sulfonylhydrazine Substitution.

A synthesis of a δ-ketohydroperoxide is described, addressing potential functional-group compatibilities in these elusive species relevant to combustion and atmospheric chemistries. The hydroperoxide is installed via sulfonylhydrazine substitution, which was found to be more effective than displacement of secondary halides. As part of this protocol, it was observed that 1,2-dimethoxyethane is an advantageous medium for the reaction, avoiding the formation of a tetrahydrofuran hydroperoxide side product. This discovery facilitated the multigram synthesis (6 steps, 41 % yield overall) and discrete characterization of the target δ-ketohydroperoxide.

Chirality Transfer and Asymmetric Catalysis: Two Strategies toward the Enantioselective Formal Total Synthesis of (+)-Gelsenicine.

Two strategies are described en route to an enantioselective total synthesis of gelsenicine. One approach centers on a chirality transfer cycloisomerization that ultimately fell short. Separately, an asymmetric catalysis route utilizing bisphosphine-gold-catalyzed cycloisomerization was pursued. A catalytic system was identified that provided a synthetic intermediate in our Gelsemium alkaloid syntheses in high enantiopurity and with absolute configuration determined by electronic circular dichroism, thus representing an enantioselective formal total synthesis of (+)-gelsenicine.

Regioselectivity Influences in Platinum-Catalyzed Intramolecular Alkyne O-H and N-H Additions.

The steric and electronic drivers of regioselectivity in platinum-catalyzed intramolecular hydroalkoxylation are elucidated. A branch point is found that divides the process between 5-exo and 6-endo selective processes, and enol ethers can be accessed in good yields for both oxygen heterocycles. The main influence arises from an electronic effect, where the alkyne substituent induces a polarization of the alkyne that leads to preferential heteroatom attack at the more electron-deficient carbon. The electronic effects are studied in other contexts, including hydroacyloxylation and hydroamination, and similar trends in directionality are predominant although not uniformly observed.

Synthesis of 1,3-Diynes via Cadiot-Chodkiewicz Coupling of Volatile, in Situ Generated Bromoalkynes.

A convenient Cadiot-Chodkiewicz protocol that facilitates the use of low molecular weight alkyne coupling partners is described. The method entails an in situ elimination from a dibromoolefin precursor and immediate subjection to copper-catalyzed conditions, circumventing the hazards of volatile brominated alkynes. The scope of this method is described, and the internal 1,3-diyne products are preliminarily evaluated in ruthenium-catalyzed azide-alkyne cycloadditions.

Cyclopentene Annulations of Alkene Radical Cations with Vinyl Diazo Species Using Photocatalysis.

A direct (3+2) cycloaddition between alkenes and vinyl diazo reagents using either Cr or Ru photocatalysis is described. The intermediacy of a radical cation species enables a nucleophilic interception by vinyl diazo compounds, a departure from their traditional electrophilic behavior. A variety of cyclopentenes are synthesized using this method, and experimental insights implicate a direct cycloaddition instead of a cyclopropanation/rearrangement process.

Establishment of Novel Biosynthetic Pathways for the Production of Salicyl Alcohol and Gentisyl Alcohol in Engineered Escherichia coli.

Salicyl alcohol and gentisyl alcohol are two important phenolic alcohols that possess significant biological activities and pharmaceutical properties. Here, we report establishment of novel biosynthetic pathways for microbial production of salicyl alcohol and gentisyl alcohol from renewable feedstocks. We first examined the promiscuity of the carboxylic acid reductase CAR toward salicylic acid and 2,5-DHBA, which enabled efficient synthesis of salicyl alcohol and gentisyl alcohol. Then, we employed a novel salicylic acid 5-hydroxylase to achieve 2,5-DHBA production from salicylic acid. After that, the de novo biosynthetic pathways were assembled and optimized by programming the carbon flux into the shikimate pathway. The final titers of salicyl alcohol and gentisyl alcohol reached to 594.4 mg/L and 30.1 mg/L, respectively. To our knowledge, this work achieved microbial production of salicyl alcohol and gentisyl alcohol for the first time. Our present study also demonstrated application of enzyme promiscuity to establish non-natural biosynthetic pathways for the production of high-value compounds.

Engineering a bacterial platform for total biosynthesis of caffeic acid derived phenethyl esters and amides.

Caffeic acid has been widely recognized as a versatile pharmacophore for synthesis of new chemical entities, among which caffeic acid derived phenethyl esters and amides are the most extensively-investigated bioactive compounds with potential therapeutical applications. However, the natural biosynthetic routes for caffeic acid derived phenethyl esters or amides remain enigmatic, limiting their bio-based production. Herein, product-directed design of biosynthetic schemes allowed the development of thermodynamically favorable pathways for these compounds via acyltransferase (ATF) mediated trans-esterification. Production based screening identified a microbial O-ATF from Saccharomyces cerevisiae and a plant N-ATF from Capsicum annuum capable of forming caffeic acid derived esters and amides, respectively. Subsequent combinatorial incorporation of caffeic acid with various aromatic alcohol or amine biosynthetic pathways permitted the de novo bacterial production of a panel of caffeic acid derived phenethyl esters or amides in Escherichia coli for the first time. Particularly, host strain engineering via systematic knocking out endogenous caffeoyl-CoA degrading thioesterase and pathway optimization via titrating co-substrates enabled production enhancement of five caffeic acid derived phenethyl esters and amides, with titers ranging from 9.2 to 369.1mg/L. This platform expanded the capabilities of bacterial production of high-value natural aromatic esters and amides from renewable carbon source via tailoring non-natural biosynthetic pathways.

Meta-Selective C-H Arylation of Aromatic Alcohols with a Readily Attachable and Cleavable Molecular Scaffold.

The first example of meta-selective C-H arylations of arene alcohol-based substrates is described. The strategy involves the combination of the transient norbornene strategy with the quinoline-based acetal scaffold to achieve the formation of biaryl compounds. Both a two-step meta-arylation/scaffold cleavage process and a total telescoping procedure are described, highlighting the convenient attributes of attachment, removal, and recovery of the acetal scaffold. Moreover, the meta-arylated compounds can be further derivatized via ortho-selective functionalizations. These processes establish a foundation for catalytic polyfunctionalization of alcohol-based compounds.

Radical Cation Cyclopropanations via Chromium Photooxidative Catalysis.

The chromium photocatalyzed cyclopropanation of diazo reagents with electron-rich alkenes is described. The transformation occurs under mild conditions and features specific distinctions from traditional diazo-based cyclopropanations (e.g., avoiding ß-hydride elimination, chemoselectivity considerations, etc.). The reaction appears to work most effectively using chromium catalysis, and a number of decorated cyclopropanes can be accessed in generally good yields.

Chromium photocatalysis: accessing structural complements to Diels-Alder adducts with electron-deficient dienophiles.

A chromium-catalyzed, visible light-activated net [4 + 2] cycloaddition between dienes and electron-deficient alkenes is described. Gathered evidence, via control experiments, isolated intermediates, and measured redox potentials, points to several converging reaction pathways that afford the cyclohexene adducts, including a photochemical [2 + 2] cycloaddition/vinylcyclobutane rearrangement cascade and a substrate excitation/oxidation sequence to a radical cation intermediate. Notably, the accompanying mechanistic stipulations result in a process that yields regioisomeric compounds from those generated by traditional Diels-Alder cycloadditions.

Platinum-Catalyzed α,ß-Unsaturated Carbene Formation in the Formal Syntheses of Frondosin B and Liphagal.

Formal syntheses of tetracyclic terpenoids frondosin B and liphagal are described. Both synthetic routes rely on the use of platinum-catalyzed α,ß-unsaturated carbene formation for the key C-C bond forming transformations. The successful route toward frondosin B utilizes a formal (4 + 3) cycloaddition, while the liphagal synthesis features the vinylogous addition of an enol nucleophile as a key step. Both synthetic routes are discussed, revealing insights into structural requirements in the catalytic α,ß-unsaturated carbene reaction manifold.

Palladium(II)-Catalyzed ortho-Arylation of Aromatic Alcohols with a Readily Attachable and Cleavable Molecular Scaffold.

A palladium(II)-catalyzed C-H arylation process of alcohols has been developed. The strategy utilizes a novel quinoline-based hemiacetal scaffold that can direct the selective C-H bond functionalization. This reaction provides a useful method to construct biaryl compounds of benzyl alcohols in good to excellent yields. The new molecular scaffold can be readily attached, removed, and recovered.

Uncovering the Roles of Oxygen in Cr(III) Photoredox Catalysis.

A combined experimental and theoretical investigation aims to elucidate the necessary roles of oxygen in photoredox catalysis of radical cation based Diels-Alder cycloadditions mediated by the first-row transition metal complex [Cr(Ph2phen)3](3+), where Ph2phen = bathophenanthroline. We employ a diverse array of techniques, including catalysis screening, electrochemistry, time-resolved spectroscopy, and computational analyses of reaction thermodynamics. Our key finding is that oxygen acts as a renewable energy and electron shuttle following photoexcitation of the Cr(III) catalyst. First, oxygen quenches the excited Cr(3+)* complex; this energy transfer process protects the catalyst from decomposition while preserving a synthetically useful 13 µs excited state and produces singlet oxygen. Second, singlet oxygen returns the reduced catalyst to the Cr(III) ground state, forming superoxide. Third, the superoxide species reduces the Diels-Alder cycloadduct radical cation to the final product and reforms oxygen. We compare the results of these studies with those from cycloadditions mediated by related Ru(II)-containing complexes and find that the distinct reaction pathways are likely part of a unified mechanistic framework where the photophysical and photochemical properties of the catalyst species lead to oxygen-mediated photocatalysis for the Cr-containing complex but radical chain initiation for the Ru congener. These results provide insight into how oxygen can participate as a sustainable reagent in photocatalysis.

C-C Bond Migration in the Cycloisomerization of 1,6-Enynes.

A full account of our investigation of C-C bond migration in the cycloisomerization of oxygen-tethered 1,6-enynes is described. Under Pt(II) and/or Ir(I) catalysis, cyclic and acylic alkyl groups were found to undergo 1,2-shifts into metal carbenoid intermediates. Interestingly, this process does not appear to be driven by the release of ring strain, and thus provides access to large carbocyclic frameworks. The beneficial effect of CO on the Pt(II) and Ir(I) catalytic systems is also evaluated.

Total Synthesis of Gelsenicine via a Catalyzed Cycloisomerization Strategy.

The first total synthesis of (±)-gelsenicine is reported. The synthetic route is highly efficient (13 steps), featuring (1) a pivotal metal-catalyzed isomerization/rearrangement process that forges the central core of the molecule and (2) two facile C-N bond-forming steps that establish the flanking heterocycles.

Lewis Acid Mediated Vinylogous Additions of Enol Nucleophiles into an α,ß-Unsaturated Platinum Carbene.

A variety of substituted indoles and benzofurans are accessed via a platinum catalyzed annulation and vinylogous addition of enol nucleophiles. Several ß-dicarbonyl compounds participate in the reaction, as do α-nitro and α-cyano carbonyl species. Subjecting the indole products to acidic conditions results in the formation of fused heterocycles.

The design of a readily attachable and cleavable molecular scaffold for ortho-selective C-H alkenylation of arene alcohols.

We describe herein the design of a novel molecular scaffold that can induce facile oxidative olefinations when attached to alcohols. Benzylic, homo-, and bishomobenzylic alcohols are utilized. The scaffold can act as a protecting group for the alcohol in other transformations, and it is recoverable in excellent yield. The overall sequence can also be telescoped without purifications of intermediates, representing a net alcohol-based directed ortho-alkenylation.