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

• resulting telescoped flow process was effectively applied across a series of acid substrates rendering the desired carbamate structures in high yield and purity. The derivatization of these products via complementary flow-based Michael addition reactions furthermore demonstrated the creation of β-amino acid

• utilizing electron-poor alkenes as the reaction partners that would undergo aza-Michael addition reactions on the Cbz-carbamates (Scheme 4). Driven by the desire to develop readily scalable routes towards the target products 8, continuous flow processing was again exploited. In a first approach the use of

• -based aza-Michael addition reactions. This novel approach allows for the creation of important chemical building blocks whilst demonstrating a new use of biocatalysts in continuous flow processes. Scope of Cbz-carbamate products obtained via flow process (*tRes = 60 min, **T = 80 °C; isolated yields

Annulation of a 1,3-dithiole ring to a sterically hindered o-quinone core. Novel ditopic redox-active ligands

• Sergey V. Norkov,
• Anton V. Cherkasov,
• Andrey S. Shavyrin,
• Maxim V. Arsenyev,
• Viacheslav A. Kuropatov and
• Vladimir K. Cherkasov

Beilstein J. Org. Chem. 2021, 17, 273–282, doi:10.3762/bjoc.17.26

• bulky sulfur-containing group. The possible pathway for the following cyclization is the Michael addition of the sulfide atom to the central carbon of the acetylacetonate group [38][39][40][41]. The X-ray diffraction study as well as IR and NMR spectroscopy data reveal that in all synthesized compounds

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

• -difluorocyclopropanecarboxylic acid derivatives 58 by the Michael addition of ester and amide enolates to 2,4,6-trimethylphenyl 4-bromo-4,4-difluorocrotonate (57) followed by an Et3B-initiated radical cyclization (Scheme 24) [68]. Furthermore, when the sodium salt of dimethyl malonate was used as the Michael donor the

Selective synthesis of α-organylthio esters and α-organylthio ketones from β-keto esters and sodium S-organyl sulfurothioates under basic conditions

• Jean C. Kazmierczak,
• Roberta Cargnelutti,
• Thiago Barcellos,
• Claudio C. Silveira and
• Ricardo F. Schumacher

Beilstein J. Org. Chem. 2021, 17, 234–244, doi:10.3762/bjoc.17.24

• -rich N-heterocycles [2][3][4], decarboxylative cross-coupling reactions with propiolic acid derivatives [5], Michael addition reaction [6], cross-couplings catalyzed by Pd [7] and Cu salts [8][9], the preparation of symmetrical and nonsymmetrical disulfides [10][11], and the synthesis of β-acetamido

Facile preparation and conversion of 4,4,4-trifluorobut-2-yn-1-ones to aromatic and heteroaromatic compounds

• Takashi Yamazaki,
• Yoh Nakajima,
• Minato Iida and
• Tomoko Kawasaki-Takasuka

Beilstein J. Org. Chem. 2021, 17, 132–138, doi:10.3762/bjoc.17.14

• ][19], we decided to employ them without further purification. The Michael addition reactions were then carried out under basic conditions for the ynone 2a thus obtained, which, to our astonishment, was found to be relatively rare even for the nonfluorinated counterparts (Table 2) [24][25][26][27][28

• slowdown of the reaction rate when tert-butylamine was employed, which was considered to be a reflection of the sensitivity of ynones 2 towards steric hindrance. Because appropriate conditions for the initial Michael addition reactions were thus determined, further conversion to the benzene derivative 4aa

• seemed to be an important factor, and the corresponding lithium and sodium salts did not aid the reaction satisfactory. Moreover, EtONa was found to be inappropriate for this protocol (Table 3, entries 10 and 11). Determination of the appropriate conditions both for Michael addition as well as

Direct synthesis of anomeric tetrazolyl iminosugars from sugar-derived lactams

• Michał M. Więcław and
• Bartłomiej Furman

Beilstein J. Org. Chem. 2021, 17, 115–123, doi:10.3762/bjoc.17.12

• as the aldol reaction [30], Michael addition [31], Mannich reaction [32], and hydrogenation [33]. Results and Discussion Quite recently Xie and Dixon showed that it is possible to synthesize α-tetrazolylamines from simple and linear tertiary amides using an iridium-based catalytic protocol [19]. They

• widely used as organocatalysts. Such moieties are employed in a number of important synthetic transformations, including the aldol reaction [30], Michael addition [31], Mannich reaction [32], and hydrogenation [33]. We plan to test these possibilities in the near future. Stereochemistry and configuration

Recent progress in the synthesis of homotropane alkaloids adaline, euphococcinine and N-methyleuphococcinine

• Dimas J. P. Lima,
• Antonio E. G. Santana,
• Michael A. Birkett and
• Ricardo S. Porto

Beilstein J. Org. Chem. 2021, 17, 28–41, doi:10.3762/bjoc.17.4

• forms. Key (homotropane construction) steps included: i) inter and intramolecular Mannich reaction; ii) double Michael addition in the cyclooctadienone derivative; and iii) intramolecular 1,3-dipolar cycloaddition. As shown in Scheme 1, the azabicyclononane ring is an interesting target for strategies

All-carbon [3 + 2] cycloaddition in natural product synthesis

• Zhuo Wang and
• Junyang Liu

Beilstein J. Org. Chem. 2020, 16, 3015–3031, doi:10.3762/bjoc.16.251

• 66b gave α,β-unsaturated amide 67, which was treated with KHMDS to facilitate an intramolecular Michael addition to give lactam 68 in quantitative yield. The conversion of freshly prepared lactam 68 to xanthante ester 69 was achieved in three steps. Exposure of xanthante ester 69 to AIBN and a

• underwent successive intramolecular Michael addition and hydrolytic nitrile reduction to give 79 in 46% yield in two steps. Extensive studies of the nitrile reduction eventually identified that Et3Al and DIBAL-H could effectively reduce the nitrile group to the corresponding aldehyde and treatment with

• intramolecular [3 + 2] cycloaddition begins with the reaction between the rhodium catalyst Rh(I)LCl and alcohol 110 to give complex A through alcoholysis [50][51] (Scheme 8B). Rh(I)-mediated retro-propargylation of the homopropargyl alcohol A afforded complex B. It undergoes an intramolecular Michael addition

Convenient access to pyrrolidin-3-ylphosphonic acids and tetrahydro-2H-pyran-3-ylphosphonates with multiple contiguous stereocenters from nonracemic adducts of a Ni(II)-catalyzed Michael reaction

• Alexander N. Reznikov,
• Dmitry S. Nikerov,
• Anastasiya E. Sibiryakova,
• Victor B. Rybakov,
• Evgeniy V. Golovin and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2020, 16, 2073–2079, doi:10.3762/bjoc.16.174

• reactions with aldehydes yielding tetrahydropyranylphosphonates as individual stereoisomers. These nonracemic heterocycles containing phosphoryl moieties are useful for designing new pharmacologically active compounds. Keywords: asymmetric catalysis; Michael addition; phosphonates; pyrrolidines

• heterocycles. The present work reports on the synthesis of nonracemic phosphoryl-substituted pyrrolidines and tetrahydropyranes via Ni(II)-catalyzed asymmetric Michael addition of β-keto phosphonates to conjugated nitroolefins. Results and Discussion For the synthesis of nonracemic polysubstituted pyrrolidin-3

• -ylphosphonic acids and tetrahydropyranylphosphonates, we assumed that the 4-nitro-2-oxophosphonates – the Michael adducts of β-keto phosphonates and nitroolefins – are suitable precursors, considering that the Ni(II)-catalyzed Michael addition was carried out not only enantioselectively, but also

Reactions of 3-aryl-1-(trifluoromethyl)prop-2-yn-1-iminium salts with 1,3-dienes and styrenes

• Thomas Schneider,
• Michael Keim,
• Bianca Seitz and
• Gerhard Maas

Beilstein J. Org. Chem. 2020, 16, 2064–2072, doi:10.3762/bjoc.16.173

• -iminium triflates R‒C≡C‒C(CF3)=N+Me2 TfO− [27]. As a first synthetic application, we have reported the phospha-Michael addition providing 3-(triphenylphosphonio)-1-(trifluoromethyl)-1-(dimethylamino)allenes, which were subsequently transformed into α-(trifluoromethyl)pyrroles. In the present paper, we

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166

• catalysts, this group found that the intramolecular oxa-Michael addition using 20 mol % of the diarylprolinol organocatalyst 37 in the presence of benzoic acid gave 38. The use of the enantiomer of 37 gave the dihydropyran with the opposite configuration at C-11. The catalytic hydrogenation of 38 proceeded

• iodine-catalyzed Mukiyama–Michael addition of the ketene silyl acetal 104 to 103 afforded the trans-1,5-disubstituted tetrahydropyranone 105. After the generation of the C-3-exocyclic olefin and functional group manipulation, the Takai olefination [40] of the aldehyde 106 gave the trans-vinyl iodide 107

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• nucleophilic addition, the authors suggested the tentative mechanism depicted in Scheme 34. As shown, γ-fluoride loss from enolate I, formed after the conjugate Michael addition, would lead to the formation of difluoroenone II. This could in turn undergo a nucleophilic addition of water, followed by a retro

Recent synthesis of thietanes

• Jiaxi Xu

Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116

Oxime radicals: generation, properties and application in organic synthesis

• Igor B. Krylov,
• Stanislav A. Paveliev,
• Alexander S. Budnikov and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2020, 16, 1234–1276, doi:10.3762/bjoc.16.107

• the C=C double bond of maleimides was reported [96]. The iminoxyl radicals were detected by EPR spectroscopy, but the non-radical mechanism (copper-catalyzed Michael addition) can not be excluded completely. Application of the oxime radicals in organic synthesis: intramolecular reactions There are two

Copper catalysis with redox-active ligands

• Agnideep Das,
• Yufeng Ren,
• Cheriehan Hessin and
• Marine Desage-El Murr

Beilstein J. Org. Chem. 2020, 16, 858–870, doi:10.3762/bjoc.16.77

• precursors affords both enantiomers Δ-10 (from CuClO4) and Λ-10 from (Cu(CH3CN)4PF6). UV–vis and circular dichroism spectroscopic studies evidence that the helical chirality exhibited by these two catalysts could be reversed by redox stimuli. These complexes could perform enantioselective Michael addition

• trifluoromethylation of heteroaromatics with redox-active iminosemiquinone ligands. Reversal of helical chirality upon redox stimuli and enantioselective Michael addition with a redox-reconfigurable copper catalyst. Interaction of guanidine-copper catalyst with oxygen and representative coupling products. a4 mol

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

• Valerian Dragutan,
• Ileana Dragutan,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2020, 16, 738–755, doi:10.3762/bjoc.16.68

• dienyne precursors in three steps, from (S)- and (R)-citronellal, through a diastereoselective Michael addition, chemoselective dibromoolefination, and a one-pot Wittig olefination/alkyne-bond formation. The enantiopure dienynes were then converted into the enantiomeric hydroazulenes in 53% and 55% yield

• enantiopure trienyne or diene–diyne metathesis precursors were readily obtained from (S)-citronellal by a highly diastereoselective organocatalytic Michael addition. Erogorgiaene An exceptionally stereoselective synthesis of erogorgiaene (12) (95% E-selectivity) was reported by Hoveyda et al. [80]. They

Design and synthesis of diazine-based panobinostat analogues for HDAC8 inhibition

• Sivaraman Balasubramaniam,
• Sajith Vijayan,
• Liam V. Goldman,
• Xavier A. May,
• Kyra Dodson,
• Sweta Adhikari,
• Fatima Rivas,
• Davita L. Watkins and
• Shana V. Stoddard

Beilstein J. Org. Chem. 2020, 16, 628–637, doi:10.3762/bjoc.16.59

• hydroxylamine was added to compound 11 in methanol, and a predominant polar spot was observed by TLC. However, the isolated product was not the expected TOI1, as 1H NMR revealed two new peaks at δ 4.53 and 2.66 ppm (Supporting Information File 1, Figure S36) presumably indicating that a favorable Michael

• addition followed by intramolecular cyclization or vice versa provided compound 12, which was validated by 13C and DEPT NMR studies (Supporting Information File 1 Figures S37and S38). Marred with these observations, compound 11 was treated with aqueous hydroxylamine in the presence of strong base (i.e., 10

Synthesis of 3-alkenylindoles through regioselective C–H alkenylation of indoles by a ruthenium nanocatalyst

• Abhijit Paul,
• Debnath Chatterjee,
• Srirupa Banerjee and
• Somnath Yadav

Beilstein J. Org. Chem. 2020, 16, 140–148, doi:10.3762/bjoc.16.16

• -anchored indole-5-carboxylic acid was successful during the homogeneous two-phase alkenylation reaction. Subsequently, during its removal from the support under alkaline conditions, N-alkylation occurred through a Michael addition to the acrylate 2a, followed by the formation of the methyl ester of the 5

A review of asymmetric synthetic organic electrochemistry and electrocatalysis: concepts, applications, recent developments and future directions

• Munmun Ghosh,
• Valmik S. Shinde and
• Magnus Rueping

Beilstein J. Org. Chem. 2019, 15, 2710–2746, doi:10.3762/bjoc.15.264

• results with α-bromocarboxylic acid derivatives 167 substituted with Oppolzer’s camphor sultam, which provided carboxylated products 168 in good yield (80%) and excellent diastereomeric ratio (98:2) (Scheme 53). The same group reported an electrocatalytic Michael addition of chiral acetoacetic derivatives

• diastereoselective Michael addition reactions [103][104]. The glycine–nickel complex 184 was deprotonated using a radical anion generated from the electrochemical reduction of azobenzene. The anionic Ni complex 185 acted as a good C-nucleophile towards Michael acceptors 186 resulting in diastereoisomeric mixtures of

• 187 and 187'. Moreover, the modified Ni-complexes obtained after Michael addition could be easily decomposed using HCl in MeOH, releasing functionalized amino acid 189 along with the quantitative recovery of the chiral auxiliary (S)-BPB 188 (Scheme 59). Recently, Kise’s group reported an efficient

Fluorinated maleimide-substituted porphyrins and chlorins: synthesis and characterization

• Valentina A. Ol’shevskaya,
• Elena G. Kononova and
• Andrei V. Zaitsev

Beilstein J. Org. Chem. 2019, 15, 2704–2709, doi:10.3762/bjoc.15.263

• covalently conjugates thiol groups of cysteine residues in proteins or peptides by the thio-Michael addition to the double bond of the maleimide to form a corresponding succinimidyl thioether. Conjugation of the cysteine sulfhydryl group with maleimide moieties allows us to prepare the bioconjugates

• conjugated to a cystein residue of serum albumin via a Michael addition reaction. At the same time, it is well known that 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin and its chlorin derivatives generate singlet oxygen by the light irradiation under atmospheric oxygen [31]. These tetrapyrrole macrocycles

Emission solvatochromic, solid-state and aggregation-induced emissive α-pyrones and emission-tuneable 1H-pyridines by Michael addition–cyclocondensation sequences

• Natascha Breuer,
• Irina Gruber,
• Christoph Janiak and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2019, 15, 2684–2703, doi:10.3762/bjoc.15.262

• Strukturchemie, Universitätsstraße 1, D-40225 Düsseldorf, Germany 10.3762/bjoc.15.262 Abstract Starting from substituted alkynones, α-pyrones and/or 1H-pyridines were generated in a Michael addition–cyclocondensation with ethyl cyanoacetate. The peculiar product formation depends on the reaction conditions as

• alkynylation–Michael addition–cyclocondensation (AMAC) multicomponent syntheses of α-pyrones [23]. While most α-pyrones neither fluoresce in solution nor in the solid state specific substitution patterns have been identified for fluorophore design for this heterocyclic family. Tominaga and co-workers

• effects of base and temperature on Michael addition–cyclocondensation sequences in the formation of α-pyrones and/or 1H-pyridines starting from diversely substituted alkynones and cyanoethylacetate. This bifurcating domino process furnishes small chromophore libraries which were characterized by

1,5-Phosphonium betaines from N-triflylpropiolamides, triphenylphosphane, and active methylene compounds

• Vito A. Fiore,
• Chiara Freisler and
• Gerhard Maas

Beilstein J. Org. Chem. 2019, 15, 2603–2611, doi:10.3762/bjoc.15.253

• their isolation and structural characterization are still less common. A very convenient access to such betaines is provided by the nucleophilic addition of tertiary phosphanes to electron-deficient alkenes, alkynes and allenes (phospha-Michael addition), which generates the betaines as reactive

• -catalyzed reactions of acetylenic ketones and esters with pinacolborane have been discussed [7][8]. The Michael addition of PPh3 at acetylenic carbonyl compounds generates phosphonium/vinyl anion intermediates which have been trapped with CH-, NH-, OH- and SH-acids [5]. In this manner, the 1:1:1 reaction of

• (Scheme 2). They turned out to be excellent substrates for transamidation reactions (reaction 1) [18], whereas tertiary phosphanes Ph2P–X (X = SiMe3, Cl) underwent Michael addition leading to silylphosphanylation (reaction 2) or hydrophosphorylation (reaction 3) of the C–C-triple bond, respectively [19

Synthetic terpenoids in the world of fragrances: Iso E Super^® is the showcase

• Alexey Stepanyuk and
• Andreas Kirschning

Beilstein J. Org. Chem. 2019, 15, 2590–2602, doi:10.3762/bjoc.15.252

• ]. Oxidation, iodocarboxylation and elimination yielded the lactone 43. A series of functional group manipulations provided enone 44, which underwent a cuprate-mediated Michael addition and liberation of the aldehyde 46 upon ozonolysis. After intramolecular aldol condensation the resulting enone 47 was

Targeted photoswitchable imaging of intracellular glutathione by a photochromic glycosheet sensor

• Xianzhi Chai,
• Hai-Hao Han,
• Yi Zang,
• Jia Li,
• Xiao-Peng He,
• Junji Zhang and
• He Tian

Beilstein J. Org. Chem. 2019, 15, 2380–2389, doi:10.3762/bjoc.15.230

• high intracellular concentration of GSH is another feature for HepG2 cells. Therefore, amounts of work on HepG2 cell imaging have targeted GSH as the characteristic biomarker [40][41]. Strategies like reduction of disulfide [42][43][44] and Michael addition [45][46][47] have been utilized to design

Synthesis of 1-azaspiro[4.4]nonan-1-oxyls via intramolecular 1,3-dipolar cycloaddition

• Yulia V. Khoroshunova,
• Denis A. Morozov,
• Andrey I. Taratayko,
• Polina D. Gladkikh,
• Yuri I. Glazachev and
• Igor A. Kirilyuk

Beilstein J. Org. Chem. 2019, 15, 2036–2042, doi:10.3762/bjoc.15.200

• and 3-nitropentane (Scheme 1). In brief, the reaction of nitrocyclohexane and acrolein in a CH3ONa/CH3OH solution afforded the corresponding nitroaldehyde 3b with a 70% yield. Of note, the Michael addition of 3-nitropentane to acrolein was accompanied by remarkable tarring and gave a much lower yield