Inline purification in continuous flow synthesis – opportunities and challenges

• Jorge García-Lacuna and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182

• group where an immobilized lipase (e.g., CALB) facilitated the derivatization of high-boiling benzyl alcohol in scaled Curtius rearrangement reactions. Ultimately, this approach negated the use of column chromatography in favor of a simple trituration process to isolate pure carbamate products [106

Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives

• Alexander Leslie,
• Thomas S. Moody,
• Megan Smyth,
• Scott Wharry and
• Marcus Baumann

Beilstein J. Org. Chem. 2021, 17, 379–384, doi:10.3762/bjoc.17.33

• flow process is presented that couples a Curtius rearrangement step with a biocatalytic impurity tagging strategy to produce a series of valuable Cbz-carbamate products. Immobilized CALB was exploited as a robust hydrolase to transform residual benzyl alcohol into easily separable benzyl butyrate. The

• species. This strategy thus highlights the applicability of this work towards the creation of important chemical building blocks for the pharmaceutical and speciality chemical industries. Keywords: biocatalysis; CALB; Curtius rearrangement; flow synthesis; reaction telescoping; Introduction Continuous

• within continuous flow processes [17][18][19][20] to provide a greener and more chemoselective means for the synthesis of drug-like targets. Recently, we reported on an innovative telescoped process using immobilized CALB (Candida antarctica lipase B) to enable the conversion of residual benzyl alcohol

Nanoreactors for green catalysis

• M. Teresa De Martino,
• Loai K. E. A. Abdelmohsen,
• Floris P. J. T. Rutjes and
• Jan C. M. van Hest

Beilstein J. Org. Chem. 2018, 14, 716–733, doi:10.3762/bjoc.14.61

• stabilized by colloidal particles that adsorb at the water–oil interface. They are more stable than classical emulsions and do not require the usage of small molecule surfactants. This is a big advantage in downstream processing and product and catalyst recovery. The enzyme Candida antarctica lipase B (CalB

• ) was encapsulated in the lumen of the polymersomes or in the Pickering emulsion water droplet. The esterification reaction of 1-hexanol and hexanoic acid was used to evaluate the catalytic performance of the CalB-loaded Pickering emulsions. Higher enzymatic activity was observed when CalB was

• recycling. Polymeric nanoreactors were also used to perform ring-opening polymerization (ROP) in water. Nallani et al. reported on the enzymatic polymerization of lactones using CalB, which was immobilized in both the polymersome lumen and bi-layer [21]. Nanoreactors for ROP were prepared from polystyrene

Position-dependent impact of hexafluoroleucine and trifluoroisoleucine on protease digestion

• Susanne Huhmann,
• Anne-Katrin Stegemann,
• Kristin Folmert,
• Damian Klemczak,
• Johann Moschner,
• Michelle Kube and
• Beate Koksch

Beilstein J. Org. Chem. 2017, 13, 2869–2882, doi:10.3762/bjoc.13.279

• assay [30]. Substitution of tryptophan, tyrosine, and phenylalanine residues in a glycosylation-deficient mutant of Candida antarctica lipase B, CalB N74D, by their monofluorinated analogues, left the resistance to proteolytic degradation by proteinase K unchanged [31]. Incorporation of α-fluoroalkyl

Correction: Mechanochemical enzymatic resolution of N-benzylated-β³-amino esters

• Mario Pérez-Venegas,
• Gloria Reyes-Rangel,
• Adrián Neri,
• Jaime Escalante and
• Eusebio Juaristi

Beilstein J. Org. Chem. 2017, 13, 2128–2130, doi:10.3762/bjoc.13.210

• under ball milling. Substrate scope for the enzymatic resolution of N-benzylated-β3-amino esters. Recycling capacity of immobilized CALB under HSBM conditions. Scaling-up of the enzymatic hydrolysis reaction under ball-milling using substrate rac-1a. Supporting Information Supporting Information File

Selective enzymatic esterification of lignin model compounds in the ball mill

• Ulla Weißbach,
• Saumya Dabral,
• Laure Konnert,
• Carsten Bolm and
• José G. Hernández

Beilstein J. Org. Chem. 2017, 13, 1788–1795, doi:10.3762/bjoc.13.173

• the advantages of enzyme catalysis and mechanochemistry. Under the described conditions, the primary aliphatic hydroxy groups present in the substrates were selectively modified by the biocatalyst to afford monoesterified products. Amongst the tested lipases, CALB proved to be the most effective

• diameter) [9], demonstrated to efficiently mediate the enzymatic kinetic resolution of secondary alcohols under solvent-free conditions in both mixer and planetary ball mills (Scheme 1b) [10]. Interestingly, this latter lipase (a commercial preparation known as Novozyme 345, hereinafter referred as CALB

• reactants were observed by 1H NMR spectroscopy. Repeating the experiment in the presence of 30 mg of the immobilized lipase CALB led to a total conversion of the erythro-1a after just 1 h. Purification of the product by column chromatography afforded the monoacetylated erythro-3a in 93% yield (Scheme 2

Mechanochemical enzymatic resolution of N-benzylated-β³-amino esters

• Mario Pérez-Venegas,
• Gloria Reyes-Rangel,
• Adrián Neri,
• Jaime Escalante and
• Eusebio Juaristi

Beilstein J. Org. Chem. 2017, 13, 1728–1734, doi:10.3762/bjoc.13.167

• resolution of racemic β3-amino esters employing Candida antarctica lipase B (CALB) to afford highly valuable enantioenriched N-benzylated-β3-amino acids in good yields. Furthermore the present protocol is readily scalable. Keywords: ball-milling; β3-amino acid; Candida antarctica lipase B; enzymatic

• CALB enzyme under high-speed ball-milling (HSBM) conditions as a method to obtain enantiopure N-benzylated-β3-amino acids (Scheme 1). Results and Discussion A racemic mixture of substrate rac-1a (82 mg, 1 equiv) was milled in an Agate jar (12 mm of diameter, 4.6 mL) with an Agate ball (6 mm of diameter

• , 480 mg weight) using water (3.6 μL, 0.5 equiv), 0.2 mL of 2-methyl-2-butanol (2M2B) as a LAG additive (η = 1.63) and 40 mg of CALB (Novozym 435, Novozymes, recombinant, expressed in Aspergillus niger, immobilized in acrylic resin, >10000 U/g) at 25 Hz during 30 min. Gratifyingly, 55% conversion to the

Flow synthesis of phenylserine using threonine aldolase immobilized on Eupergit support

• Jagdish D. Tibhe,
• Hui Fu,
• Timothy Noël,
• Qi Wang,
• Jan Meuldijk and
• Volker Hessel

Beilstein J. Org. Chem. 2013, 9, 2168–2179, doi:10.3762/bjoc.9.254

• difficulty of enzyme recovery. Recently, Wang et al. have shown that the activity and recyclability of the CalB enzyme can be enhanced by the use of a polymersome Pickering emulsion. As such, a biphasic system could be used by loading the enzyme in the aqueous phase and organic reagents in the polymersome [3

Efficient and selective chemical transformations under flow conditions: The combination of supported catalysts and supercritical fluids

• M. Isabel Burguete,
• Eduardo García-Verdugo and
• Santiago V. Luis

Beilstein J. Org. Chem. 2011, 7, 1347–1359, doi:10.3762/bjoc.7.159

• Antarctica lipase B (CALB) as the biocatalyst (Scheme 9). In the case of the work by Leitner and Reetz, the CALB enzyme was suspended in a bulk IL phase. At 45 °C and 10.5 MPa and using a substrate:donor ratio of 0.5 they achieved conversions of 43–50% with 99% ee values for the acetate. In a further

• the corresponding bulk ILs [109]. CALB supported on those SILLPs was shown to be an efficient and very stable catalyst for the continuous flow synthesis of citronellyl propionate in scCO2. The presence of a high IL/enzyme ratio is reflected in a high stabilization of the CALB in those systems. Thus

• –98% [110][111]. Essentially enantiopure products with at least 80% yields were obtained with supported CALB as the biocatalyst. Similarly, the synthesis of DKR phenylethanol can be performed by the combination of the two catalysts in a “one pot” single columnar minireactor. This was packed with a

Development of dynamic kinetic resolution on large scale for (±)-1-phenylethylamine

• Lisa K. Thalén and
• Jan-E. Bäckvall

Beilstein J. Org. Chem. 2010, 6, 823–829, doi:10.3762/bjoc.6.97

• Lisa K. Thalen Jan-E. Backvall Stockholm University, Department of Organic Chemistry, Arrhenius Laboratory SE-106 91, Stockholm, Sweden 10.3762/bjoc.6.97 Abstract Candida antarctica lipase B (CALB) and racemization catalyst 4 were combined in the dynamic kinetic resolution (DKR) of (±)-1

• -phenylethyl)acetamide (3) in good yield and high ee when alkyl methoxyacetates were used as acyl donors compared to when isopropyl acetate was used as the acyl donor. The catalyst loading could be decreased to 1.25 mol % Ru-catalyst 4 and 10 mg CALB per mmol 1 when alkyl methoxyacetates were used as the acyl

• (CALB) as the enzyme and 4 as the racemization catalyst (See Scheme 1 for an example of the previously developed protocol with isopropyl acetate as the acyl donor providing 2 as the amide product) [12][13]. The Jacobs–De Vos group showed that palladium on an alkaline earth support in combination with an

Large- scale ruthenium- and enzyme- catalyzed dynamic kinetic resolution of (rac)-1-phenylethanol

• Krisztián Bogár,
• Belén Martín-Matute and
• Jan-E. Bäckvall

Beilstein J. Org. Chem. 2007, 3, No. 50, doi:10.1186/1860-5397-3-50

• -phenylethanol (2) is addressed. The immobilized lipase Candida antarctica lipase B (CALB) was employed for the resolution, which shows high enantioselectivity in the transesterification. The ruthenium catalyst used, (η 5-C5Ph5)RuCl(CO)2 1, was shown to possess very high reactivity in the "in situ" redox

• chemistry.[27] In the course of the chemo-enzymatic synthesis of optically pure alcohols and esters, Candida antarctica lipase B (CALB) was found to be one of the most active and selective biocatalysts compared to other enzymes. Lipases do not need the presence of a cofactor and they can be employed in pure

• organic solvents.[38][39] CALB is immobilized on polyacrylate and this increases its thermostability and makes it easy to recover from the reaction mixture. Recently, we have developed highly efficient DKR protocols for secondary alcohols in which the traditional enzymatic resolution is combined with an