Best practices in heterotrophic high-cell-density microalgal processes: achievements, potential and possible limitations

Microalgae of numerous heterotrophic genera (obligate or facultative) exhibit considerable metabolic versatility and flexibility but are currently underexploited in the biotechnological manufacturing of known plant-derived compounds, novel high-value biomolecules or enriched biomass. Highly efficient production of microalgal biomass without the need for light is now feasible in inexpensive, well-defined mineral medium, typically supplemented with glucose. Cell densities of more than 100 g l−1 cell dry weight have been achieved with Chlorella, Crypthecodinium and Galdieria species while controlling the addition of organic sources of carbon and energy in fedbatch mode. The ability of microalgae to adapt their metabolism to varying culture conditions provides opportunities to modify, control and thereby maximise the formation of targeted compounds with non-recombinant microalgae. This review outlines the critical aspects of cultivation technology and current best practices in the heterotrophic high-cell-density cultivation of microalgae. The primary topics include (1) the characteristics of microalgae that make them suitable for heterotrophic cultivation, (2) the appropriate chemical composition of mineral growth media, (3) the different strategies for fedbatch cultivations and (4) the principles behind the customisation of biomass composition. The review confirms that, although fundamental knowledge is now available, the development of efficient, economically feasible large-scale bioprocesses remains an obstacle to the commercialisation of this promising technology

A Reductive-Heck Approach to the Hydroazulene Ring System: A Formal Synthesis of the Englerins

The reduction of a palladium enolate prior to β-hydride elimination provides a unique reaction for the synthesis of the hydroazulene ring system. When combined with a transannular epoxide rearrangement cascade, the reductive-Heck reaction allows rapid entry to the oxo-bridged guaiane core of the englerins

A Reductive-Heck Approach to the Hydroazulene Ring System: A Formal Synthesis of the Englerins

The reduction of a palladium enolate prior to β-hydride elimination provides a unique reaction for the synthesis of the hydroazulene ring system. When combined with a transannular epoxide rearrangement cascade, the reductive-Heck reaction allows rapid entry to the oxo-bridged guaiane core of the englerins

Iron-Catalyzed Cross-Coupling Reactions of Alkyl Grignards with Aryl Sulfamates and Tosylates

The iron-catalyzed cross-coupling of aryl sulfamates and tosylates has been achieved with primary and secondary alkyl Grignards. This study of iron-catalyzed cross-coupling reactions also examines the isomerization and β-hydride elimination problems that are associated with the use of isopropyl nucleophiles. While a variety of iron sources were competent in the reaction, the use of FeF₃•3H₂O was critical to minimize nucleophile isomerization

Iron-Catalyzed Coupling of Aryl Sulfamates and Aryl/Vinyl Tosylates with Aryl Grignards

The iron-catalyzed coupling of aryl sulfamates and tosylates with aryl Grignard reagents is reported for the first time. The methodology employs air-stable, low-cost FeF₃·3H₂O and the N-heterocyclic carbene ligand IPr·HCl as the preligand to form a long-lived catalyst upon treatment with aryl Grignards. The reaction provides a range of cross-coupled products in good-to-excellent yields. In contrast to previous reports with aryl chlorides, these reactions proceed with low levels of Grignard homocoupling regardless of the iron source

Manganese-Catalyzed Borylation of Unactivated Alkyl Chlorides

The use of low-cost manganese­(II) bromide (MnBr₂) and tetramethyl­ethylene­diamine (TMEDA) catalyzes the cross coupling of (bis)­pinacolato­diboron with a wide range of alkyl halides, demonstrating the first manganese-catalyzed coupling with alkyl electrophiles. This method allows access to primary, secondary, and tertiary boronic esters from the parent chlorides, which were previously inaccessible as coupling partners. The reaction proceeds in high yield with as little as 1000 ppm catalyst loading, while 5 mol % can provide high yields in as little as 30 min. Finally, radical-clock experiments revealed that at 0 °C direct borylation outcompetes alternative radical processes, thereby providing synthetically useful, temperature-controlled reaction outcomes

Iron-Catalyzed Arene Alkylation Reactions with Unactivated Secondary Alcohols

A simple, iron-based catalytic system allows for the inter- and intramolecular arylation of unactivated secondary alcohols. This transformation expands the substrate scope beyond the previously required activated alcohols and proceeds under mild reaction conditions, tolerating air and moisture. Furthermore, the use of an enantioenriched secondary alcohol provides an enantioenriched product for the intramolecular reaction, thereby offering a convenient approach to nonracemic products

A Unified Strategy for Iron-Catalyzed <i>ortho</i>-Alkylation of Carboxamides

Using 8-aminoquinoline-based aryl carboxamides, the direct <i>ortho-</i>alkylation can be achieved in high yields in the presence of an iron source, 1,2-bis­(diphenyl­phosphino)­ethane (dppe) and phenyl­magnesium bromide. The reactions proceed without overalkylation and provide high levels of regioselectivity. The benzylation reactions can be performed in air with reagent-grade THF, while the alkylation works well with unactivated secondary bromides and iodides in 2-methyl­tetrahydro­furan. Moreover, the reactions only require 5–10 min

Iron-Catalyzed, Fluoroamide-Directed C–H Fluorination

This communication describes a mild, amide-directed fluorination of benzylic, allylic, and unactivated C–H bonds mediated by iron. Upon exposure to a catalytic amount of iron­(II) triflate (Fe­(OTf)₂), <i>N</i>-fluoro-2-methylbenzamides undergo chemoselective fluorine transfer to provide the corresponding fluorides in high yield. The reaction demonstrates broad substrate scope and functional group tolerance without the use of any noble metal additives. Mechanistic and computational experiments suggest that the reaction proceeds through short-lived radical intermediates with F-transfer mediated directly by iron