Das Arzneimittel Efavirenz ist wichtig für die Behandlung von HIV, aber für Millionen von Menschen nicht zugänglich. Hier wird ein neues halbkontinuierliches Verfahren vorgestellt, das die Herstellung von rac-Efavirenz in 45 % Ausbeute ermöglicht. Die optimierte, beispielhafte Synthese basiert auf dem effizienten, kupferkatalysierten Aufbau eines Arylisocyanats und einer anschließenden intramolekularen Cyclisierung zur Einführung des Carbamatkerns von Efavirenz in einem Schritt. Die dreistufige Sequenz stellt die kürzeste Synthese dieses lebenswichtigen Arzneistoffes dar.

While continuous chemical processes have attracted both academic and industrial interest, virtually all active pharmaceutical ingredients (APIs) are still produced by using multiple distinct batch processes. To date, methods for the divergent multistep continuous production of customizable small molecules are not available. A chemical assembly system was developed, in which flow-reaction modules are linked together in an interchangeable fashion to give access to a wide breadth of chemical space. Control at three different levels—choice of starting material, reagent, or order of reaction modules—enables the synthesis of five APIs that represent three different structural classes (γ-amino acids, γ-lactams, β-amino acids), including the blockbuster drugs Lyrica and Gabapentin, in good overall yields (49–75 %).

Efavirenz is an essential medicine for the treatment of HIV, which is still inaccessible to millions of people worldwide. A novel, semi-continuous process provides rac-Efavirenz with an overall yield of 45 %. This streamlined proof-of-principle synthesis relies on the efficient copper-catalyzed formation of an aryl isocyanate and a subsequent intramolecular cyclization to install the carbamate core of Efavirenz in one step. The three-step method represents the shortest synthesis of this life-saving drug to date.

Während kontinuierliche chemische Prozesse in der akademischen Forschung und der Industrie untersucht werden, werden nach wie vor praktisch alle pharmazeutisch aktiven Wirkstoffe (APIs; active pharmaceutical ingredients) über eine Abfolge einzelner Batchprozesse hergestellt. Methoden für die divergente, mehrstufige kontinuierliche Produktion von niedermolekularen Verbindungen sind bislang nicht verfügbar. Wir beschreiben hier die Entwicklung eines chemischen Fertigungssystems bestehend aus austauschbaren Durchflussreaktionsmodulen, das einen großen chemischen Strukturraum zugänglich macht. Die Steuerung des Gesamtprozesses auf drei Ebenen – durch die Wahl des Ausgangsmaterials, der Reagentien oder der Reihenfolge der Module – ermöglichte die Synthese von fünf APIs als Vertreter dreier unterschiedlicher Strukturklassen (γ-Aminosäuren, γ-Lactame, β-Aminosäuren), einschließlich der Bestseller-Medikamente Lyrica und Gabapentin, in guten Gesamtausbeuten (49–75 %).

Due to the narrow width of tubing/reactors used, photochemistry performed in micro- and mesoflow systems is significantly more efficient than when performed in batch due to the Beer-Lambert Law. Owing to the constant removal of product and facility of flow chemical scalability, the degree of degradation observed is generally decreased and the productivity of photochemical processes is increased. In this Personal Account, we describe a wide range of photochemical transformations we have examined using both visible and UV light, covering cyclizations, intermolecular couplings, radical polymerizations, as well as singlet oxygen oxygenations.

A new tridentate bifunctional chelator, N-(-2-picolyl)(-4-hydroxy)(-3-amino)benzoic acid (PHAB), was designed to efficiently coordinate the [^99mTc(CO)₃]⁺ core and facilitate coupling reactions to biomolecules. The chelator can be procured in the form of the corresponding benzotriazole ester (PHAB-OBT), which can be stored and used as a bioconjugation kit. PHAB-OBT reacts with modified carbohydrates with high selectivity and efficiency in a single step in both aqueous and organic media. As is desirable for a kit, no complicated chemical bench work is required. Glycoconjugate postlabeling resulted in neutral radiolabeled glycans with high radiochemical yields. Prelabeling approaches were assessed by successive reaction of PHAB-OBT with the [^99mTc(CO)₃]⁺ core and a modified galactose model. The radiolabeled galactose was obtained in 84 % yield as defined by HPLC analysis. Biodistribution of the radioactive ^99mTc-labeled chelator, as well as the glycoconjugates, were examined in mice. Noticeably different biodistribution patterns were observed that reflect trends in the uptake of carbohydrate analogues by various organs.

Primary and secondary amines can be rapidly and quantitatively oxidized to the corresponding imines by singlet oxygen. This reactive form of oxygen was produced using a variable-temperature continuous-flow LED-photoreactor with a catalytic amount of tetraphenylporphyrin as the sensitizer. α-Aminonitriles were obtained in good to excellent yields when trimethylsilyl cyanide served as an in situ imine trap. At 25°C, primary amines were found to undergo oxidative coupling prior to cyanide addition and yielded secondary α-aminonitriles. Primary α-aminonitriles were synthesized from the corresponding primary amines for the first time, by an oxidative Strecker reaction at –50 °C. This atom-economic and protecting-group-free pathway provides a route to racemic amino acids, which was exemplified by the synthesis of tert-leucine hydrochloride from neopentylamine.

Primäre und sekundäre Amine können mit Singulettsauerstoff schnell und quantitativ zu den entsprechenden Iminen oxidiert werden. Ein temperierbarer, LED-betriebener Durchflussphotoreaktor produziert in Gegenwart katalytischer Mengen Tetraphenylporphyrin als Sensibilisator die reaktive Form des Sauerstoffs. α-Aminonitrile konnten mit Trimethylsilylcyanid als In-situ-Abfangreagens in guten bis ausgezeichneten Ausbeuten hergestellt werden. Primäre Amine reagierten bei 25 °C aufgrund oxidativer Kupplung vor der Cyanidaddition zu den sekundären α-Aminonitrilen. Überraschenderweise konnten erstmals primäre α-Aminonitrile synthetisiert werden, indem die oxidative Strecker-Reaktion bei −50 °C durchgeführt wurde. Dieser Prozess kann zur atomökonomischen und schutzgruppenfreien Herstellung racemischer Aminosäuren genutzt werden, was am Beispiel der Synthese von tert-Leucinhydrochlorid aus Neopentylamin gezeigt wird.

Poly/oligo(amidoamine)s (PAAs) have recently been recognised for their potential as well-defined scaffolds for multiple carbohydrate presentation and as multivalent ligands. Herein, we report two complimentary strategies for the preparation of such sequence-defined carbohydrate-functionalised PAAs that use photochemical thiolene coupling (TEC) as an alternative to the established azide–alkyne cycloaddition (“click”) reaction. In the first approach, PAAs that contained multiple olefins were synthesised on a solid support from a new building block and subsequent conjugation with unprotected thio-carbohydrates. Alternatively, a pre-functionalised building block was prepared by using TEC and assembled on a solid support to provide a carbohydrate-functionalised PAA. Both methods rely on the use of a continuous flow photoreactor for the TEC reactions. This system is highly efficient, owing to its short path length, and requires no additional radical initiator. Performing the reactions at 254 nm in Teflon AF-2400 tubing provides a highly efficient TEC procedure for carbohydrate conjugation, as demonstrated in the reactions of O-allyl glycosides with thiols. This method allowed the complete functionalisation of all of the reactive sites on the PAA backbone in a single step, thereby obtaining a defined homogeneous sequence. Furthermore, reaction at 366 nm in FEP tubing in the flow reactor enabled the large-scale synthesis of an fluorenylmethyloxycarbonyl (Fmoc)-protected glycosylated building block, which was shown to be suitable for solid-phase synthesis and will also allow heterogeneous sequence control of different carbohydrates along the oligomeric backbone. These developments enable the synthesis of sequence-defined carbohydrate-functionalised PAAs with potential biological applications.

The first total synthesis of the O-antigen pentasaccharide repeating unit from Gram-negative bacteria Escherichia coli O111 was achieved starting from four monosaccharide building blocks. Key to the synthetic approach was a bis-glycosylation reaction to combine trisaccharide 10 and colitose 5. The colitose building block (5) was obtained de novo from non-carbohydrate precursors. The pentasaccharide was equipped at the reducing end with an amino spacer to provide a handle for subsequent conjugation to a carrier protein in anticipation of immunological studies.

Carbohydrates on cell surfaces are critical components of the extracellular landscape and contribute to cell signalling, motility, adhesion and recognition. Multivalent effects are essential to these interactions that are inherently weak. Carbohydrate-functionalised surfaces meet an important need for studying the multivalent interactions between carbohydrates and other biomolecules. Innovations in nanomaterials are revolutionising how these carbohydrate interfaces are studied and underscore their importance in the cosmos of biochemical interactions.

Isolation of the most effective antimalarial drug, artemisinin, from the plant sweet wormwood, does not yield sufficient quantities to provide the more than 300 million treatments needed each year. The high prices for the drug are a consequence of the unreliable and often insufficient supply of artemisinin. Large quantities of ineffective fake drugs find a market in Africa. Semisynthesis of artemisinin from inactive biological precursors, either dihydroartemisinic acid (DHAA) or artemisinic acid, offers a potentially attractive route to increase artemisinin production. Conversion of the plant waste product, DHAA, into artemisinin requires use of photochemically generated singlet oxygen at large scale. We met this challenge by developing a one-pot photochemical continuous-flow process for the semisynthesis of artemisinin from DHAA that yields 65 % product. Careful optimization resulted in a process characterized by short residence times. A method to extract DHAA from the mother liquor accumulated during commercial artemisinin extractions, a material that is currently discarded as waste, is also reported. The synthetic continuous-flow process described here is an effective means to supplement the limited availability of artemisinin and ensure increased supplies of the drug for those in need.

A new method for the spatially defined alignment of carbohydrates on a duplex DNA scaffold is presented. The use of an N-hydroxysuccinimide (NHS)-ester phosphoramidite along with carbohydrates containing an alkylamine linker allows for on-column labeling during solid-phase oligonucleotide synthesis. This modification method during solid-phase synthesis only requires the use of minimal amounts of complex carbohydrates. The covalently attached carbohydrates are presented in the major groove of the B-form duplex DNA as potential substrates for murine type II C-type lectin receptors mMGL1 and mMGL2. CD spectroscopy and thermal melting revealed only minimal disturbance of the overall helical structure. Surface plasmon resonance and cellular uptake studies with bone-marrow-derived dendritic cells were used to assess the capability of these carbohydrate-modified duplexes to bind to mMGL receptors.

Galectins are a class of carbohydrate-binding proteins named for their galactose-binding preference and are involved in a host of processes ranging from homeostasis of organisms to immune responses. As a first step towards correlating the carbohydrate-binding preferences of the different galectins with their biological functions, we determined carbohydrate recognition fine-specificities of galectins with the aid of carbohydrate microarrays. A focused set of oligosaccharides considered relevant to galectins was prepared by chemical synthesis. Structure–activity relationships for galectin–sugar interactions were determined, and these helped in the establishment of redundant and specific galectin actions by comparison of binding preferences. Distinct glycosylations on the basic lactosyl motifs proved to be key to galectin binding regulation—and therefore galectin action—as either high-affinity ligands are produced or binding is blocked. High-affinity ligands such as the blood group antigens that presumably mediate particular functions were identified.