High-throughput experimentation (HTE) has revolutionized the pharmaceutical industry, most notably allowing for rapid screening of compound libraries against therapeutic targets. The past decade has ...also witnessed the extension of HTE principles toward the realm of small-molecule process chemistry. Today, most major pharmaceutical companies have created dedicated HTE groups within their process development teams, invested in automation technology to accelerate screening, or both. The industry’s commitment to accelerating process development has led to rapid innovations in the HTE space. This review will deliver an overview of the latest best practices currently taking place within our teams in process chemistry by sharing frequently studied transformations, our perspective for the next several years in the field, and manual and automated tools to enable experimentation. A series of case studies are presented to exemplify state-of-the-art workflows developed within our laboratories.
Here, we present a novel continuous flow approach for the Wadsworth–Emmons cyclopropanation of alkyl-substituted chiral epoxides into chiral cyclopropane carboxylic acids. The developed flow process ...circumvents the risks associated with the harsh conditions (high T/P) required, considering the highly volatile nature of the epoxide-SM. Additionally, the flow reactors offer increased efficiency, as their reduced headspace contributes to keeping a higher concentration of the low-boiling-point reactants in the liquid phase and thus enhanced reactivity, contrary to the use of sealed vessels in batch. The cyclopropane formation process is coupled with in-line workup and hydrolysis transformations to yield the desired enantiomerically pure cyclopropane carboxylic acids in good yields up to the 100 g scale.
We describe herein a two-step process for the conversion of serine to a wide array of optically pure unnatural amino acids. This method utilizes a photocatalytic cross-electrophile coupling between a ...bromoalkyl intermediate and a diverse set of aryl halides to produce artificial analogues of phenylalanine, tryptophan, and histidine. The reaction is tolerant of a broad range of functionalities and can be leveraged toward the scalable synthesis of valuable pharmaceutical scaffolds via flow technology.
Photoredox catalysis has emerged as a powerful and versatile platform for the synthesis of complex molecules. While photocatalysis is already broadly used in small-scale batch chemistry across the ...pharmaceutical sector, recent efforts have focused on performing these transformations in process chemistry due to the inherent challenges of batch photocatalysis on scale. However, translating optimized batch conditions to flow setups is challenging, and a general approach that is rapid, convenient, and inexpensive remains largely elusive. Herein, we report the development of a new approach that uses a microscale high-throughput experimentation (HTE) platform to identify optimal reaction conditions that can be directly translated to flow systems. A key design point is to simulate the flow-vessel pathway within a microscale reaction plate, which enables the rapid identification of optimal flow reaction conditions using only a small number of simultaneous experiments. This approach has been validated against a range of widely used photoredox reactions and, importantly, was found to translate accurately to several commercial flow reactors. We expect that the generality and operational efficiency of this new HTE approach to photocatalysis will allow rapid identification of numerous flow protocols for scale.
Critical parameters affecting the stereoselective amination of (hetero)aromatic ketones using transaminases have been studied, such as temperature, pH, substrate concentration, cosolvent, and source ...and percentage of amino donor, to further optimize the production of enantiopure amines using both (S)- and (R)-selective biocatalysts from commercial suppliers. Interesting enantiopure amino building blocks have been obtained, overcoming some limitations of traditional chemical synthetic methods. Representative processes were scaled up, affording halogenated and heteroaromatic amines in enantiomerically pure form and good isolated yields.
The diastereoselective preparation of cis- or trans-4-substituted-4-aminocyclohexyl alcohols by conventional chemical processes reported in the literature requires long synthetic sequences and is not ...amenable to scale-up. In the past decade, ketoreductases (KREDs) have emerged as a powerful approach for the preparation of chiral secondary alcohols from prochiral ketones. This paper describes the diastereoselective preparation at the kilo scale of cis-allyl N-(4-hydroxy-1-methyl-cyclohexyl)carbamate (6a) via ketoreductase transformation. The methodology was also applicable to a set of different analogous cyclic ketones.
The synthesis of enantiopure C‐12 methoxy‐ or alkyl‐substituted 5,7,8,12b‐tetrahydro4helicene quinones 16 and 17 and the 7,8‐dihydroaromatic analogues 4 and 5 has been achieved from ...(SS)‐2‐(p‐tolylsulfinyl)‐1,4‐benzoquinone. In the first series, with a structure containing both central and helical chiralities, the R absolute configuration of the stereogenic carbon atom was defined after the asymmetric cycloaddition step, whereas the P or M helicity was shown to be dependent on the nature of the C‐12 substituent. The size of this group was also defining the configurational stability of the final (P)‐7,8‐dihydro4helicene quinones 4 and 5. The interconversion barriers between the P and M helimers in the latter, computed with a DFT B3LYP method, matched well with the experimentally observed stability. Our study provided evidence that, in addition to steric effects, a small but significant role of electronic effects is governing the configurational stability of such helical quinones.
La síntesis asimétrica de las 5,7,8,12b‐tetrahidro4heliceno quinonas metoxi o alquil sustituídas en C‐12, 16 y 17, y las análogas 7,8‐dihidroaromáticas 4 y 5 se ha llevado a cabo a partir de la (S,S)‐2‐(p‐tolilsulfinil)‐1,4‐benzoquinona. En las quinonas 16 y 17, que poseen quiralidad central y helicoidal, la configuración absoluta R en el carbono estereogénico se define después de la etapa de cicloadición asimétrica, mientras que la helicidad P o M depende de la naturaleza del sustituyente en C‐12. El tamaño de este grupo es fundamental a la hora de definir la estabilidad configuracional de las (P)‐7,8‐dihidro4heliceno quinonas 4 y 5. Las barreras de interconversión entre los helímeros P y M de 4 y 5, calculadas teóricamente con el método DFT B3LYP, coincidieron bastante bien con la estabilidad configuracional observada experimentalmente. Este estudio ha evidenciado que, además de efectos estéricos, existe una pequeña pero significativa contribución de efectos electrónicos para explicar la estabilidad configuracional de estas quinonas helicoidales.
An effective chirality transfer from an enantiopure sulfinyl quinone allows the one‐pot preparation of tetrahydro4helicene quinones, which contain both central and helical chiralities, with excellent optical purities or dihydro4helicene derivatives, which contain only helical chirality (see scheme). In the latter, the configurational stability is mainly controlled by the size of the substituent at C‐12.
A series of γ-butyrolactone derivatives, including some spiranic ones, was obtained through desymmetrization of the corresponding prochiral 3-substituted cyclobutanones via Baeyer–Villiger ...monooxygenase (BVMO)-catalyzed oxidation. After reaction optimization using several commercial enzymes, both antipodes of various lactones were synthesized in most cases with >90% conversion and >80% enantiomeric excess under mild reaction conditions. In some cases alcohol formation was also observed (up to 40% conversion) as an undesired side reaction due to the presence of alcohol dehydrogenases in these preparations. Selected transformations were achieved on a 100 mg scale showing the possibilities of these oxidative biocatalysts as a new source of highly interesting compounds.
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The reaction of 1,4‐divinyl‐1,3‐cyclohexadiene, 5,8‐dimethoxy‐ or tert‐butyldimethylsilyloxy‐3‐vinyl‐1,2‐dihydrophenanthrene or 6‐vinyl‐7,8‐dihydro‐1,4‐phenanthrenequinone with an excess of ...enantiopure (SS)‐2‐(p‐tolylsulfinyl)‐1,4‐benzoquinone (2) led to the direct formation of enantioenriched dihydro5helicenequinones or bisquinones (50→98 % ee). A domino Diels–Alder cycloaddition/sulfoxide elimination/partial aromatization process occurs, being the absolute configuration of the final helicene defined in the aromatization step. Both M and P helimers are accessible through a stepwise enantiodivergent process if the pentacyclic dihydroaromatic intermediate resulting in the two first steps is aromatized in the presence of (±)‐2, DDQ, CAN or DBU.
La reacción de 1,4‐divinil‐1,3‐ciclohexadieno, 5,8‐dimetoxi‐ o terc‐butildimetilsililoxi‐3‐vinil‐1,2‐dihidrofenantreno o 6‐vinil‐7,8‐dihidro‐1,4‐fenantrenoquinona con exceso de (SS)‐2‐(p‐tolilsulfinil)‐1,4‐benzoquinona (2) condujo a la formación de dihidro5helicenoquinonas o bisquinonas enantioméricamente enriquecidas (50→98 % ee) a través de un proceso dominó en el que tiene lugar una reacción de Diels–Alder y una eliminación pirolítica del sulfóxido seguidas de una etapa de aromatización del derivado dihidroaromatico resultante. La configuración absoluta del heliceno final se define en la etapa de aromatización. En un proceso por etapas enantiodivergente, es posible acceder a los dos helímeros (M) y (P) por tratamiento del precursor dihidroaromatico pentacíclico con (±)‐2, DDQ, CAN o DBU.
An effective chirality transfer is achieved in the domino cycloaddition/sulfoxide elimination/partial aromatization process between enantiomerically pure sulfinylbenzoquinone (SS)‐1 and differently substituted vinyl dihydrophenanthrenes, affording in a stereodivergent way; depending on the conditions, the P or M enantiomers of the corresponding dihydro5helicenequinones were obtained in good to excellent optical yields.
The resolution of different mandelic acids using the lipase PS “Amano” SD enzyme is described. By supporting the lyophilized enzyme over Celite, both the activity and the stability of lipase PS in ...organic media were significantly improved, enabling the robust resolution scale-up of 3-fluoromandelic acid. The methodology was extended to produce a range of optically pure (R)-mandelic acids, avoiding tedious extractions or chromatography.
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