Functions of enzyme domains in 2-methylisoborneol biosynthesis and enzymatic synthesis of non-natural analogs

• Binbin Gu,
• Lin-Fu Liang and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 1452–1459, doi:10.3762/bjoc.19.104

• studied. Several 2-methylisoborneol synthases have a proline-rich N-terminal domain of unknown function. The results presented here demonstrate that this domain leads to a reduced enzyme activity, in addition to its ability to increase long-term solubility of the protein. Furthermore, the substrate scope

• versions of 2MIBSs exhibit a proline-rich N-terminal domain of unknown function that appears disordered in the crystal structure [28]. As a first aspect of this study, we have investigated the possible function of this N-terminal domain. 2MIBS is known to form several methylated monoterpenes as side

• changed alkylation pattern. Results and Discussion Function of the proline-rich N-terminal domain of 2MIBS S. coelicolor 2MIBS was selected to investigate the function of the proline-rich N-terminal domain (hereafter termed A domain, the C-terminal domain is named as domain B). Based on a sequence

One-pot nucleophilic substitution–double click reactions of biazides leading to functionalized bis(1,2,3-triazole) derivatives

• Hans-Ulrich Reissig and
• Fei Yu

Beilstein J. Org. Chem. 2023, 19, 1399–1407, doi:10.3762/bjoc.19.101

• presence of sodium ascorbate as reducing agent and sodium carbonate as base as well as ʟ-proline as ligand in a DMF/water mixture at 60 °C provided this promising result. These conditions applied are similar to those described by Fokin et al. [24], which had also been employed by other groups [37][38]. The

• allowed to lower the reaction temperature from 60 °C to 40 °C, but it also induced full consumption of the intermediate biazide derived from dihalide 11 (Scheme 4, reaction 3); 0.2 equiv of copper(II) sulfate pentahydrate, 0.4 equiv of sodium ascorbate and 0.4 equiv of ʟ-proline in very little of

A new oxidatively stable ligand for the chiral functionalization of amino acids in Ni(II)–Schiff base complexes

• Alena V. Dmitrieva,
• Oleg A. Levitskiy,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2023, 19, 566–574, doi:10.3762/bjoc.19.41

• give rise to additional dispersion interactions with the phenyl ring in the proline auxiliary, making the Schiff base complexes more conformationally rigid, thus increasing the stereochemical outcome of the functionalized amino acids as compared to the parent ligand L1. In the present paper, the new

• . Results and Discussion Synthesis The synthetic approach to the chiral ligand L7 as well as to its Ni–Schiff base derivatives containing glycine, serine, dehydroalanine, and cysteine is given in Scheme 2. Commercially available (S)-proline was used as the starting material. To obtain the starting t-Bu

• benzyl fragment was observed. This indicated that H-2 is located on the same side of the nickel coordination plane as the benzyl substituent at the proline nitrogen atom, leading to the ʟ-configuration of the α-amino acid stereocenter. Notably, the major stereoisomer of all thiolated compounds (RCysNi)L7

NaI/PPh₃-catalyzed visible-light-mediated decarboxylative radical cascade cyclization of N-arylacrylamides for the efficient synthesis of quaternary oxindoles

• Dan Liu,
• Yue Zhao and
• Frederic W. Patureau

Beilstein J. Org. Chem. 2023, 19, 57–65, doi:10.3762/bjoc.19.5

• reported a Ru(bpy)3Cl2-catalyzed synthesis of N-Boc proline oxindole derivatives under visible-light assistance [47]. Therein, N-hydroxyphthalimide (NPhth) esters were utilized as alkyl radical precursors, which can be readily prepared from highly available carboxylic acids. In 2015, Cheng and co-workers

Reductive opening of a cyclopropane ring in the Ni(II) coordination environment: a route to functionalized dehydroalanine and cysteine derivatives

• Oleg A. Levitskiy,
• Olga I. Aglamazova,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2022, 18, 1166–1176, doi:10.3762/bjoc.18.121

• Figure 2). The protons of the ester group linked to the cyclopropane moiety exhibit correlation with the methylene protons of proline in the NOESY spectrum. Thus, the ester groups are at the same side of the Ni coordination plane as the proline methylene groups indicating the (S) configuration of the α

• tolyl substituent in the side chain of the amino acid moiety and H-12 and H-13 protons of the proline methylene group is observed in the NOESY spectrum (Figure 4). Hence, the amino acid side chain and the proline methylenes are at the same side of the Ni coordination plane allowing to assign the

Heterogeneous metallaphotoredox catalysis in a continuous-flow packed-bed reactor

• Wei-Hsin Hsu,
• Susanne Reischauer,
• Peter H. Seeberger,
• Bartholomäus Pieber and
• Dario Cambié

Beilstein J. Org. Chem. 2022, 18, 1123–1130, doi:10.3762/bjoc.18.115

• a narrower residence time distribution and higher yields (see Table 2). C–O coupling reaction Finally, we evaluated the use of the capillary-based reactor for the related C–O coupling of 4-iodobenzotrifluoride and N-(Boc)-proline with N-tert-butylisopropylamine (BIPA) in dimethyl sulfoxide (DMSO

• )-proline. Optimization of temperature and light intensity for the coupling of 4-iodobenzotrifluoride and sodium p-toluenesulfinate. Comparison of different reactors. Supporting Information Supporting Information File 104: Details of packed-bed assembly, experimental procedures, reaction optimization and

Synthesis of bis-spirocyclic derivatives of 3-azabicyclo[3.1.0]hexane via cyclopropene cycloadditions to the stable azomethine ylide derived from Ruhemann's purple

• Alexander S. Filatov,
• Olesya V. Khoroshilova,
• Anna G. Larina,
• Vitali M. Boitsov and
• Alexander V. Stepakov

Beilstein J. Org. Chem. 2022, 18, 769–780, doi:10.3762/bjoc.18.77

• and cannot be isolated as individual compounds. At the same time, the reaction of ninhydrin and proline results in the formation of the stable azomethine ylide. This 1,3-dipole demonstrated high reactivity towards diverse cyclopropenes, including parent cyclopropene [22]. Note that the reactions of

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• materials to inductively heat up glass reactors. For the Biginelli reaction solubility of the starting urea (22) as well as the products 24a and 24b were an issue being overcome by using a solvent mixture of PEG/DMF 1:1. Also the proline-catalyzed asymmetric Mannich reaction was achieved with cyclohexanone

BINOL as a chiral element in mechanically interlocked molecules

• Matthias Krajnc and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2022, 18, 508–523, doi:10.3762/bjoc.18.53

• amino acids N-Boc-leucine, N-Boc-proline, and N-Boc-tryptophane were used. Overall, rotaxane 64a shows lower association constants (K = 138–2589 M−1) with preference for the (R)-isomers of the guest molecules (K(S)/K(R) = 0.29–0.66). In contrast, rotaxane 64b preferentially binds the (S)-isomers (K(S)/K

Synthesis of 3,4,5-trisubstituted isoxazoles in water via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, β-ketoesters, or β-ketoamides

• Md Imran Hossain,
• Md Imdadul H. Khan,
• Seong Jong Kim and
• Hoang V. Le

Beilstein J. Org. Chem. 2022, 18, 446–458, doi:10.3762/bjoc.18.47

• other solvents. The results are summarized in Table 1. In our first attempt, DBU or (S)-proline in 5% water, 95% methanol yielded a complex mixture of products that were not easy to distinguish (Table 1, entries 1 and 2). The use of NaHCO3 in 98% water, 2% methanol after 3 hours, produced 14% of the

New advances in asymmetric organocatalysis

• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 240–242, doi:10.3762/bjoc.18.28

• been recognized as chiral organocatalysts as early as 1912, the concept was at the periphery of the attention of synthetic organic chemists. An initial flash of interest appeared in the 1970s when proline was shown to catalyze the Robinson annulation [1][2], but this seminal work seemed to come too

• disclosed important discoveries with proline and imidazolidinones as ample chiral catalysts for aldol [7][8], Diels–Alder [9], dipolar cycloaddition [10], and Mannich reactions [11]. The organic chemistry community this time took a tremendous interest in this concept, which led to many valuable developments

Organocatalytic asymmetric nitroso aldol reaction of α-substituted malonamates

• Ekta Gupta,
• Narendra Kumar Vaishanv,
• Sandeep Kumar,
• Raja Krishnan Purshottam,
• Ruchir Kant and
• Kishor Mohanan

Beilstein J. Org. Chem. 2022, 18, 217–224, doi:10.3762/bjoc.18.25

• metal-catalyzed reactions [31][32][33][34][35][36]. The most successful among them are the ʟ-proline-catalyzed reactions of enolizable aldehydes with nitrosoarenes [37][38][39][40][41][42][43]. Besides ʟ-proline and its derivatives, various secondary amines derived from BINOL and cinchona alkaloids were

• squaramide catalyst 3c, however, with low enantioselectivity (Table 1, entry 6). Disappointingly, the reaction catalyzed by ʟ-proline-derived catalysts gave very low enantioselectivity (Table 1, entries 7 and 8). Having identified Takemoto’s catalyst as the most efficient one for this transformation, our

Synthesis and late stage modifications of Cyl derivatives

• Phil Servatius and
• Uli Kazmaier

Beilstein J. Org. Chem. 2022, 18, 174–181, doi:10.3762/bjoc.18.19

• , epimerization is prevented through deprotonation of amide NH bonds, as argued by Seebach for Li enolates [53][54]. Nevertheless, isoleucine was prone to epimerize under the reaction conditions due to its vicinity to proline and therewith lack of the “protecting” NH group. Since no full conversion was observed

Highly stereocontrolled total synthesis of racemic codonopsinol B through isoxazolidine-4,5-diol vinylation

• Lukáš Ďurina,
• Anna Ďurinová,
• František Trejtnar,
• Ľuboš Janotka,
• Lucia Messingerová,
• Jana Doháňošová,
• Ján Moncol and
• Róbert Fischer

Beilstein J. Org. Chem. 2021, 17, 2781–2786, doi:10.3762/bjoc.17.188

• -methoxycinnamaldehyde (6). Thus, the reaction of 6 with N-Cbz-protected hydroxylamine 7 catalyzed by ᴅʟ-proline in chloroform gave racemic 5-hydroxyisoxazolidine 8 in 77% yield almost as a sole trans isomer (dr > 9:1). Its structure was confirmed by comparison with already reported NMR data for the known (3S,5S

• )-enantiomer [18]. We have used ᴅʟ-proline for three reasons: first, it provides the target compounds 1 and 2 in their racemic form, second, it is able to catalyze the conjugate addition between N-EWG-protected hydroxylamines and enals effectively, and third, based on our experience, the products obtained by

• the proline catalysis are of higher purity (after purification by silica gel column chromatography), than those synthesized by other methods [16]. Definitely, the effective asymmetric organocatalytic conjugate additions of hydroxylamines to enals using various catalysts provide access to

N-Sulfinylpyrrolidine-containing ureas and thioureas as bifunctional organocatalysts

• Viera Poláčková,
• Dominika Krištofíková,
• Boglárka Némethová,
• Renata Górová,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2021, 17, 2629–2641, doi:10.3762/bjoc.17.176

• has proven to be a successful concept in asymmetric organocatalysis [2][3][4][5][6][7][8]. An amine unit with a hydrogen-bond donating skeleton is highly efficient from among various possible combinations of catalytic moieties within an organocatalyst. This idea has been inspired by proline catalysis

• sulfur stereogenic center does not play an important role in the Michael addition (Figure 3b). The stereochemical outcome of the Michael addition is dictated mainly by the configuration of the proline unit. The calculated transition states for the Michael addition with both diastereomeric catalysts (S,R

• . Sulfinylurea catalysts were more active than the corresponding thioureas. The additional stereogenic center on the sulfur plays only a minor role on the stereoselectivity of the reaction, which is governed mainly by the configuration of the proline moiety. DFT calculations elucidated the stereochemical action

Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• different approach for the use of cinchona-based organocatalysts. Instead of using the cinchona derivative alone, they employed a mixture of cinchona derivative and amino acid such as ᴅ-proline, termed as the modularly designed organocatalyst (MDO) for the synthesis of bridged tetrahydroisoquinoline

• (quinidinethiourea + ᴅ-proline), instead of the expected domino Mannich/Michael product, the bridged tetrahydroisoquinoline product 25a was obtained in high yield (90%) and excellent dr (94:6) and ee value (99%) (Table 5). The controlled reactions using 23 and 24 as the catalyst gave the product in very poor yield

• , i.e., to assist in 1,3-prototropic shift. 2.2 Catalysis by chiral pyrrolidine derivatives Chiral pyrrolidine derivatives, such as (S)-proline are widely used as organocatalysts [54][64]. Lee et al. synthesized bromopyrrole alkaloids 107 via aza-Michael addition of 4,5-dibromo-1H-pyrrole-2-carbonitrile

Constrained thermoresponsive polymers – new insights into fundamentals and applications

• Patricia Flemming,
• Alexander S. Münch,
• Andreas Fery and
• Petra Uhlmann

Beilstein J. Org. Chem. 2021, 17, 2123–2163, doi:10.3762/bjoc.17.138

Recent advances in the syntheses of anthracene derivatives

• Giovanni S. Baviera and
• Paulo M. Donate

Beilstein J. Org. Chem. 2021, 17, 2028–2050, doi:10.3762/bjoc.17.131

• reaction also included anthraquinones 173b and 173c, obtained in good yields (74–94%) [73]. In 2015, in a related approach, Lee et al. disclosed a direct one-pot synthesis of anthraquinones and tetracenediones by using ʟ-proline as organocatalyst and benzoic acid as additive (Scheme 40) [74]. They

• synthesized substituted anthraquinones bearing Me, Et, or hydroxy groups, such as compounds 176a–e, in moderate to good yields (45–94%) through a [4 + 2] cycloaddition reaction of 1,4-substituted naphthoquinones 174 and α,β-unsaturated aldehydes 175 catalyzed by ʟ-proline. During optimization studies, the

• -Proline-catalyzed [4 + 2] cycloaddition reaction of naphthoquinones and α,β-unsaturated aldehydes. Iridium-catalyzed [2 + 2 + 2] cycloaddition of a 1,2-bis(propiolyl)benzene derivative with alkynes. Synthesis of several anthraquinone derivatives by using InCl3 and molecular iodine. Indium-catalyzed

Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• stereogenic centers. Review A plethora of highly effective small‐molecule organocatalysts have enriched the field of organic synthesis [27], including chiral proline derivatives, N‐heterocyclic carbenes, chiral thioureas and Brønsted acids as well as phase‐transfer catalysts (PTC), such as the quaternary

• starting material in the asymmetric organocatalyzed reaction, the Enders group described the use of (S)-proline as catalyst in an intramolecular aldol reaction, enabling a new strategy to obtain coumarin natural products [34]. As for example, the total synthesis of (+)-smyrindiol (17), a linear

• dihydrofuranocoumarin isolated from the roots of Smyrniopsis aucheri, was developed [35]. The 5-enolexo aldol key step of this synthesis was performed using 40 mol % of (S)-proline and the desired product 14 was obtained in good yield (71%), and high diastereo- and enantioselectivities (Scheme 4). Moreover, the natural

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• amino acids and peptide scaffolds compatible with the transformation. The late-stage oxidation of proline 76 to 5-hydroxyproline furnished interesting intermediates, giving access to relevant motifs in peptide chemistry (Scheme 27C). Sesquiterpenes are known to present complex polycyclic structures with

Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

• Mathias B. Danielsen and
• Jesper Wengel

Beilstein J. Org. Chem. 2021, 17, 1828–1848, doi:10.3762/bjoc.17.125

• relative to the downregulation of the reference ASO (Oblimersen) [91]. In an entirely different approach, the 2’-amino group of amino-LNA-thymine (amino-LNA-T) has been explored as an attachment point for various cationic groups. As one example, amino acids such as glycine, lysine, and proline in different

• out for the synthesis of stereochemically pure PS-ONs and one of these methods employs the proline-derived bicyclic oxazaphospholidine monomer [122] which was later used in the scalable synthetic process of therapeutic stereopure PS-ASOs [123]. When the modified ONs were hybridized with their

Natural products in the predatory defence of the filamentous fungal pathogen Aspergillus fumigatus

• Jana M. Boysen,
• Nauman Saeed and
• Falk Hillmann

Beilstein J. Org. Chem. 2021, 17, 1814–1827, doi:10.3762/bjoc.17.124

• . They occur most often in Aspergillus and Penicillium species [160]. Fumitremorgin A (20), B (21) and C (22) can all be found in A. fumigatus (Figure 7). They are based on the precursers ʟ-tryptophan and ʟ-proline and are further derived from breviamide F, proposedly via tryprostatin B which is

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• late-stage methylation of complex drug derivatives, such as of indoprofen (anti-inflammatory), tedizolid (antibiotic), and celecoxib (anti-inflammatory), successfully delivered methylated drug candidates 22f–h, respectively. In addition, methylation of proline-containing multipeptides was achieved via

A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• -modified MCM-41 (ClCH2-MCM-41). In the next step, ʟ-proline-modified MCM-41 (ʟ-proline-MCM-41) was produced by the treatment of ClCH2-MCM-41 with N-Boc-trans-4-hydroxy-ʟ-proline in THF in the presence of NaH as base, which was then deprotected using TFA in CH2Cl2. In the last step, the immobilized copper

• complex (ʟ-proline-MCM-41-CuCl) was obtained by the reaction of ʟ-proline-MCM-41 with CuCl in acetone at mild temperature (Scheme 21) [51]. A possible mechanism for this reaction is shown in Scheme 22. Initially, copper(I)-substituted acetylide intermediate 70 is produced via the reaction of copper

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• ). Natural products like α and β-pinene that contain an olefinic moiety were also used as substrates, and these afforded ring-opened products like 89e, thereby corroborating a radical mechanism hypothesis [111]. Enantiopure substrates, like limonene oxide (88f) and the proline derivative 88h, afforded the