Desymmetrization of difluoromethylene groups by C-F bond activation.

Tertiary stereogenic centres containing one fluorine atom are valuable for medicinal chemistry because they mimic common tertiary stereogenic centres containing one hydrogen atom, but they possess distinct charge distribution, lipophilicity, conformation and metabolic stability1-3. Although tertiary stereogenic centres containing one hydrogen atom are often set by enantioselective desymmetrization reactions at one of the two carbon-hydrogen (C-H) bonds of a methylene group, tertiary stereocentres containing fluorine have not yet been constructed by the analogous desymmetrization reaction at one of the two carbon-fluorine (C-F) bonds of a difluoromethylene group3. Fluorine atoms are similar in size to hydrogen atoms but have distinct electronic properties, causing C-F bonds to be exceptionally strong and geminal C-F bonds to strengthen one another4. Thus, exhaustive defluorination typically dominates over the selective replacement of a single C-F bond, hindering the development of the enantioselective substitution of one fluorine atom to form a stereogenic centre5,6. Here we report the catalytic, enantioselective activation of a single C-F bond in an allylic difluoromethylene group to provide a broad range of products containing a monofluorinated tertiary stereogenic centre. By combining a tailored chiral iridium phosphoramidite catalyst, which controls regioselectivity, chemoselectivity and enantioselectivity, with a fluorophilic activator, which assists the oxidative addition of the C-F bond, these reactions occur in high yield and selectivity. The design principles proposed in this work extend to palladium-catalysed benzylic substitution, demonstrating the generality of the approach.

Photo- and Cobalt-Catalyzed Synthesis of Heterocycles via Cycloisomerization of Unactivated Olefins.

We report a general, intramolecular cycloisomerization of unactivated olefins with pendant nucleophiles. The reaction proceeds under mild conditions and tolerates ethers, esters, protected amines, acetals, pyrazoles, carbamates, and arenes. It is amenable to N-, O-, as well as C-nucleophiles, yielding a number of different heterocycles including, but not limited to, pyrrolidines, piperidines, oxazolidinones, and lactones. Use of both a benzothiazinoquinoxaline as organophotocatalyst and a Co-salen catalyst obviates the need for stoichiometric oxidant or reductant. We showcase the utility of the protocol in late-stage drug diversification and synthesis of several small natural products.

Iron-Mediated Photochemical Anti-Markovnikov Hydroazidation of Unactivated Olefins.

Unactivated olefins are converted to alkyl azides with bench-stable NaN3 in the presence of FeCl3·6H2O under blue-light irradiation. The products are obtained with anti-Markovnikov selectivity, and the reaction can be performed under mild ambient conditions in the presence of air and moisture. The transformation displays broad functional group tolerance, which renders it suitable for functionalization of complex molecules. Mechanistic investigations are conducted to provide insight into the hydroazidation reaction and reveal the role of water from the iron hydrate as the H atom source.

Intermolecular Organophotocatalytic Cyclopropanation of Unactivated Olefins.

Intermolecular cyclopropanation of mono-, di-, and trisubstituted olefins with α-bromo-ß-ketoesters and α-bromomalonates under organophotocatalysis is reported. The reaction displays broad functional group tolerance, including substrates bearing acids, alcohols, halides, ethers, ketones, nitriles, esters, amides, carbamates, silanes, stannanes, boronic esters, as well as arenes, and furnishes highly substituted cyclopropanes. The transformation may be performed in the presence of air and moisture with 0.5 mol % of a benzothiazinoquinoxaline as organophotocatalyst. Mechanistic investigations, involving Stern-Volmer quenching, quantum yield determination, and deuteration experiments, are carried out, and a catalytic cycle for the transformation is discussed.

Total Synthesis of (+)-Euphorikanin A via an Atropospecific Cascade.

A total synthesis of the ingenane-derived diterpenoid (+)-euphorikanin A is described. Key to the strategy is a stereocontrolled one-pot sequence consisting of transannular aldol addition reaction, hemiketal formation, and subsequent semipinacol rearrangement that efficiently leads to the complete euphorikanin skeleton. Atroposelective ring-closing olefin metathesis proved critical for the stereospecific cascade, leading to formation of a (Z)-bicyclo[7.4.1]tetradecenone core. An additional salient feature of the route is pyrolysis of a bis-methylxanthate to cleanly furnish the natural product.

Heterophenoquinones: Tuning Optoelectronics and Electrochromicity.

We report the synthesis and optoelectronic properties of 16 thiophene-based heterophenoquinones. These compounds were accessed in a convergent and modular approach, allowing for their efficient synthesis. Tuning of the optical band gap was achieved through π-extension by annulation of a benzene or tropone moiety to the thiophene, oxidation, change of the heteroatom or by attachment of a donor substituent to the thiophene core. The resulting compounds display intense colors covering the entire visible spectrum. We identified structure-property relationships and their impact on the HOMO and LUMO levels. Additionally, these materials change color upon reduction and according to in situ ultraviolet-visible-near infrared (UV-vis-NIR) and electron paramagnetic resonance (EPR) spectro-electrochemistry, they are promising electrochromes with cathodic color changes. Seven different electrochromic devices were constructed which all displayed a change in color upon reduction, demonstrating the potential of these new dyes in for example tintable glass.

Enantioselective Total Synthesis of (+)-Aberrarone.

We disclose the first total synthesis of (+)-aberrarone, a diterpenoid natural product featuring a 5-5-5-6-fused tetracyclic skeleton. Key to the approach is a Au-catalyzed-Sn-mediated Meyer-Schuster-Nazarov-cyclopropanation-aldol cascade, which closes four rings in high yield. The convergent approach furnishes the natural product (+)-aberrarone stereoselectively in 15 steps. We highlight the benefits of using a Sn-alkoxide to considerably expand the opportunities of Au-catalysis for the synthesis of complex molecules.

Transition-Metal-Catalyzed Monofluoroalkylation: Strategies for the Synthesis of Alkyl Fluorides by C-C Bond Formation.

Alkyl fluorides modulate the conformation, lipophilicity, metabolic stability, and pKa of compounds containing aliphatic motifs and, therefore, have been valuable for medicinal chemistry. Despite significant research in organofluorine chemistry, the synthesis of alkyl fluorides, especially chiral alkyl fluorides, remains a challenge. Most commonly, alkyl fluorides are prepared by the formation of C-F bonds (fluorination), and numerous strategies for nucleophilic, electrophilic, and radical fluorination have been reported in recent years. Although strategies to access alkyl fluorides by C-C bond formation (monofluoroalkylation) are inherently convergent and complexity-generating, they have been studied less than methods based on fluorination. This Review provides an overview of recent developments in the synthesis of chiral (enantioenriched or racemic) secondary and tertiary alkyl fluorides by monofluoroalkylation catalyzed by transition-metal complexes. We expect this contribution will illuminate the potential of monofluoroalkylations to simplify the synthesis of complex alkyl fluorides and suggest further research directions in this growing field.

Enantioselective Total Synthesis of (+)-Euphorikanin A.

We disclose the first total synthesis of (+)-euphorikanin A, an ingenane-derived natural product featuring an unprecedented 5/6/7/3-fused tetracyclic skeleton. Key to the approach is a SmI2-mediated ketyl-enoate reaction that leads to the formation of two rings in a single step. The polarity-reversed cyclization proceeds in excellent yield and high diastereoselectivity. Access to ring B is effected late in the synthesis by implementation of a number of chemoselective transformations, including in situ generation of a vinyl lithium species and subsequent intramolecular attack onto an α-ketolactone.

Organophotocatalytic carbo-heterofunctionalization of unactivated olefins with pendant nucleophiles.

We report the difunctionalization of unactivated, terminal olefins through intermolecular addition of α-bromoketones, -esters, and -nitriles followed by formation of 4- to 6-membered heterocycles with pendant nucleophiles. The reaction can be conducted with alcohols, acids, and sulfonamides as nucleophiles furnishing products bearing 1,4 functional group relationships that offer various handles for further manipulation. Salient features of the transformations are the use of 0.5 mol% of a benzothiazinoquinoxaline organophotoredox catalyst and their robustness with respect to air and moisture. Mechanistic investigations are carried out and a catalytic cycle for the reaction is proposed.