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

• 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

• into benzyl butyrate in view of facilitating the downstream purification of continuous flow Curtius rearrangement reactions [21]. In this paper, we will give a full account on this valuable approach and showcase the utility of the carbamate products towards generating sets of β-amino acid species

Novel library synthesis of 3,4-disubstituted pyridin-2(1H)-ones via cleavage of pyridine-2-oxy-7-azabenzotriazole ethers under ionic hydrogenation conditions at room temperature

• Romain Pierre,
• Anne Brethon,
• Sylvain A. Jacques,
• Aurélie Blond,
• Sandrine Chambon,
• Sandrine Talano,
• Catherine Raffin,
• Branislav Musicki,
• Claire Bouix-Peter,
• Loic Tomas,
• Gilles Ouvry,
• Rémy Morgentin,
• Laurent F. Hennequin and
• Craig S. Harris

Beilstein J. Org. Chem. 2021, 17, 156–165, doi:10.3762/bjoc.17.16

• morpholine amide 7. The synthesis started by selective SNAr reaction with 4 and tert-butyl ((cis)-4-aminocyclohexyl)carbamate affording the intermediate nicotinic acid 5 in 70% yield without the need for chromatography. Subsequent amide coupling using TBTU afforded 2-chloro precursor 6 in excellent yield

• ((cis)-3-aminocyclobutyl)carbamate afforded the undesired regioisomer 28 as the majority product (Scheme 5). As we were unable to exploit intermediate 26, we turned our attention to the pyridine-2-(1H)-one building block 30, easily prepared by hydrolysis of the C-2–F bond in high yield and without the

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

•  26B). The reaction conditions were also amenable to carbamates, affording the products 64–67 in moderate to good yield (42–58%). That the carbamate oxygen atom could direct the fluorination α to itself instead of α to the amide nitrogen atom provided an inverted, complementary selectivity as expected

Synthesis of monophosphorylated lipid A precursors using 2-naphthylmethyl ether as a protecting group

• Jundi Xue,
• Ziyi Han,
• Gen Li,
• Khalisha A. Emmanuel,
• Cynthia L. McManus,
• Qiang Sui,
• Dongmian Ge,
• Qi Gao and
• Li Cai

Beilstein J. Org. Chem. 2020, 16, 1955–1962, doi:10.3762/bjoc.16.162

• prepared from the common building block 15 through multiple protecting group manipulations (Scheme 2). The N-Troc group in 15 was removed by treatment with zinc in a mixture of acetic acid and CH2Cl2. The resulting amine 16 was protected immediately as fluorenylmethylenoxy (Fmoc) carbamate by reaction with

Facile synthesis of 7-alkyl-1,2,3,4-tetrahydro-1,8-naphthyridines as arginine mimetics using a Horner–Wadsworth–Emmons-based approach

• Rhys A. Lippa,
• John A. Murphy and
• Tim N. Barrett

Beilstein J. Org. Chem. 2020, 16, 1617–1626, doi:10.3762/bjoc.16.134

• of base (6 equiv) was required to overcome stalling of the olefination process. Reduction to compound 16 using benzenesulfonyl hydrazide (generating diimide in situ) proceeded in 80% yield and was followed by single-pot carbamate and phosphonate deprotection to afford arginine mimetic 6 in 86% yield

Synthesis of 3-substituted isoxazolidin-4-ols using hydroboration–oxidation reactions of 4,5-unsubstituted 2,3-dihydroisoxazoles

• Lívia Dikošová,
• Júlia Laceková,
• Ondrej Záborský and
• Róbert Fischer

Beilstein J. Org. Chem. 2020, 16, 1313–1319, doi:10.3762/bjoc.16.112

• -dichloroethane. Finally, the subsequent basic hydrolysis with 6 M NaOH [39] in isopropyl alcohol [41] to remove the carbamate readily afforded the desired isoxazolidine 12 in good yield (72%). The progress of the reaction was easily followed by TLC (EtOAc), and the N-unsubstituted isoxazolidin-4-ol 12 was

• ), 129.7 (CH-Ph), 133.7 (CH-Ph), 157.1 (CO2CH2), 165.9 (COPh); HRMS (ESI) (m/z): [M + H]+ calcd for C16H19Cl3NO5, 410.0324; found 410.0329. Hydrolysis of trichloroethyl carbamate (±)-3-Isopropylisoxazolidin-4-ol (12): The NaOH solution (0.6 mL, 3.6 mmol, 6 M) was added to a solution of the N-Troc

Copper-catalysed alkylation of heterocyclic acceptors with organometallic reagents

• Yafei Guo and
• Syuzanna R. Harutyunyan

Beilstein J. Org. Chem. 2020, 16, 1006–1021, doi:10.3762/bjoc.16.90

• efficient one to achieve an enantioselectivity of up to 96% ee. Interestingly, piperidones with different carbamate protecting groups (Me, Et, Ph, tosyl, and Bn, respectively) were tolerated, and a high enantioselectivity could also be obtained with several other dialkylzinc reagents (e.g., iPr2Zn and n

p-Pyridinyl oxime carbamates: synthesis, DNA binding, DNA photocleaving activity and theoretical photodegradation studies

• Panagiotis S. Gritzapis,
• Panayiotis C. Varras,
• Nikolaos-Panagiotis Andreou,
• Katerina R. Katsani,
• Konstantinos Dafnopoulos,
• George Psomas,
• Zisis V. Peitsinis,
• Alexandros E. Koumbis and
• Konstantina C. Fylaktakidou

Beilstein J. Org. Chem. 2020, 16, 337–350, doi:10.3762/bjoc.16.33

• Inorganic Chemistry, Chemistry Department, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece Laboratory of Organic Chemistry, Chemistry Department, Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece 10.3762/bjoc.16.33 Abstract A number of p-pyridinyl oxime carbamate

• DNA damage, whereas the substituent of the carbamate group was critical, with the halogenated derivatives to be able to cause extensive single and double stranded DNA cleavages, acting as “synthetic nucleases”, independently of oxygen and pH. Calf thymus–DNA affinity studies showed a good-to-excellent

• studies seem to allow the prediction of the activity of derivatives able to pass intersystem crossing to their triplet energy state and thus create radicals able to damage DNA. With this study, it is shown that oxime carbamate derivatives have the potential to act as novel effective photobase generating

Rapid, two-pot procedure for the synthesis of dihydropyridinones; total synthesis of aza-goniothalamin

• Thomas J. Cogswell,
• Craig S. Donald and
• Rodolfo Marquez

Beilstein J. Org. Chem. 2020, 16, 135–139, doi:10.3762/bjoc.16.15

• )-(+)-goniothalamin 2 and acylated aza-goniothalamin analogue 3 [14][15][16][17][18]. Extension of the two-pot methodology to include a variety of different aldehyde starting materials. One pot synthesis of benzyl carbamate 4 reported by Veenstra and co-workers [19]. Formation of diene 5 in 66% through a one pot

Synthesis and characterization of bis(4-amino-2-bromo-6-methoxy)azobenzene derivatives

• David Martínez-López,
• Amirhossein Babalhavaeji,
• Diego Sampedro and
• G. Andrew Woolley

Beilstein J. Org. Chem. 2019, 15, 3000–3008, doi:10.3762/bjoc.15.296

• , resulting in a yellowish oil. This was purified by column chromatography using hexane/ethyl acetate, 4:1, v/v as eluent. The product, phenol tert-butyl (4-chloro-2-hydroxyphenyl)carbamate, was used directly in the next step. (2) tert-Butyl (4-chloro-2-hydroxyphenyl)carbamate (2 mmol, 500 mg) was dissolved

• brown oil. This was poured into water and extracted three times with DCM. The organic fractions were collected and evaporated under reduced pressure. The product, tert-butyl (4-chloro-2-methoxyphenyl)carbamate, was used directly in the next step. (3) tert-Butyl (4-chloro-2-methoxyphenyl)carbamate (400

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

• mepivacaine (197a) [107]. The key steps in the synthesis involved the initial anodic oxidation of cyclic N-carbamate 194 bearing an 8-phenylmenthyl group as a chiral auxiliary which generates in situ N-acyliminium ion 195 and this 195 upon reaction with nucleophilic CN− in presence of catalytic TMSOTf and β

AgNTf₂-catalyzed formal [3 + 2] cycloaddition of ynamides with unprotected isoxazol-5-amines: efficient access to functionalized 5-amino-1H-pyrrole-3-carboxamide derivatives

• Ziping Cao,
• Jiekun Zhu,
• Li Liu,
• Yuanling Pang,
• Laijin Tian,
• Xuejun Sun and
• Xin Meng

Beilstein J. Org. Chem. 2019, 15, 2623–2630, doi:10.3762/bjoc.15.255

• 10ka–na were obtained in 50–98% yields. In addition, the Ts protecting group could be changed for other sulfonyl groups such as Ms (10na, 98%), o-Ns (10oa, 99%) and p-Ns (10pa, 99%), while the cyclic carbamate-derived ynamides such as 4q are no good substrates, leading to the formation of a complex

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

• Iwona E. Głowacka,
• Aleksandra Trocha,
• Andrzej E. Wróblewski and
• Dorota G. Piotrowska

Beilstein J. Org. Chem. 2019, 15, 1722–1757, doi:10.3762/bjoc.15.168

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

Electrophilic oligodeoxynucleotide synthesis using dM-Dmoc for amino protection

• Shahien Shahsavari,
• Dhananjani N. A. M. Eriyagama,
• Bhaskar Halami,
• Vagarshak Begoyan,
• Marina Tanasova,
• Jinsen Chen and
• Shiyue Fang

Beilstein J. Org. Chem. 2019, 15, 1116–1128, doi:10.3762/bjoc.15.108

• protections, which contained a tertiary butyl carbamate moiety, were not completely stable under the acidic conditions needed for de-tritylation in each synthetic cycle. Once the protection was lost, in the coupling step, incoming phosphoramidites would react with the free amino groups, and branched ODNs

Diaminoterephthalate–α-lipoic acid conjugates with fluorinated residues

• Leon Buschbeck,
• Aleksandra Markovic,
• Gunther Wittstock and
• Jens Christoffers

Beilstein J. Org. Chem. 2019, 15, 981–991, doi:10.3762/bjoc.15.96

• α-lipoic acid (ALA) residue. Furthermore, a fluorine-substituted moiety bound to DAT shall facilitate detection by XPS. Results and Discussion Synthesis. The preparation of DAT–ALA conjugate 3 with a fluorinated residue started from mono-carbamate-protected diethyl DAT 1 (Scheme 1). Compound 1 was

• in [44], TFA (3 mL) was added dropwise to a cooled (ice-water bath) solution of carbamate 2 (0.402 mmol, 205 mg) in CH2Cl2 (3 mL). The mixture was stirred for 19 h at ambient temperature and then poured into saturated aqueous NaHCO3 solution (50 mL). After stirring for 5 min at ambient temperature

• -(trifluoromethyl)benzylamino]terephthalate (8): Under exclusion of air and moisture, morpholine (1.17 mmol, 102 mg, 5.0 equiv) was added to a solution of carbamate 6 (0.234 mmol, 129 mg, 1.0 equiv) in abs. CH2Cl2 (3 mL). The mixture was degassed (three cycles of freeze, pump and thaw). Then Pd(PPh3)4 (12 µmol, 14

New α- and β-cyclodextrin derivatives with cinchona alkaloids used in asymmetric organocatalytic reactions

• Iveta Chena Tichá,
• Simona Hybelbauerová and
• Jindřich Jindřich

Beilstein J. Org. Chem. 2019, 15, 830–839, doi:10.3762/bjoc.15.80

• –Hillman and aldol-type reactions, we focused on their application in the decarboxylative asymmetric allylic amination (AAA) [38] of MBH carbamate 12 affording the product 13 with enantiomeric excesses of up to 75% (Scheme 4). However, compared with the published procedure [38] (up to 97% ee, aromatic

• the decarboxylative asymmetric allylic amination of a Morita–Baylis–Hillman carbamate (10 mol % of catalyst, up to 75% ee, up to 76% isolated yield). We believe that these new CD derivatives comprising cinchona alkaloids will be suitable catalysts of other asymmetric reactions using them under green

• -N3-β-CD (7) and propargylated cinchona alkaloids 3a–d. Synthesis of difunctionalized α-CD 11 with quinine moieties. AAA reaction of MBH carbamate 12 catalyzed by the prepared CD derivatives 4a–d, 5a–d, 8a–d, 9a–d, 11. Optimized conditions of the CuAAC click reactions of non-methylated azido-CDs with

A diastereoselective approach to axially chiral biaryls via electrochemically enabled cyclization cascade

• Hong Yan,
• Zhong-Yi Mao,
• Zhong-Wei Hou,
• Jinshuai Song and
• Hai-Chao Xu

Beilstein J. Org. Chem. 2019, 15, 795–800, doi:10.3762/bjoc.15.76

• imidazopyridine-containing biaryls via central-to-axial chirality transfer (Scheme 1). Results and Discussion The substituents on the phenyl ring (R1) and at the propargylic position (R2) of carbamate 2 were varied to study their effects on the diastereoselectivity (Table 1). The electrolysis was conducted under

• Et4NBF4 (1 equiv) as the supporting electrolyte. These investigations indicated that bulky tertiary groups at both R1 and R2 positions were needed to ensure efficient chirality transfer. Hence, carbamate 2a (Table 1, entry 1) bearing a t-Bu group at R1 and R2 positions, respectively, reacted to give

• the electrosynthesis was investigated by varying the peripheral substituents of the carbamate substrate 2 (Scheme 2). The pyridyl ring could be substituted at positions 4, 5 and 6 with a range of substituents with diverse electronic properties such as OMe (3e), Br (3f), CF3 (3g), CN (3h), Cl (3i), and

Cyclopropene derivatives of aminosugars for metabolic glycoengineering

• Jessica Hassenrück and
• Valentin Wittmann

Beilstein J. Org. Chem. 2019, 15, 584–601, doi:10.3762/bjoc.15.54

• and their suitability for MGE. Three mannosamine derivatives in which the cyclopropene moiety is attached to the sugar by either an amide or a carbamate linkage and that differ by the presence or absence of a stabilizing methyl group at the double bond have been examined. We determined their DAinv

• conditions. From these experiments, it became obvious that N-(cycloprop-2-en-1-ylcarbonyl)-modified (Cp-modified) mannosamine has the highest metabolic acceptance. However, carbamate-linked N-(2-methylcycloprop-2-en-1-ylmethyloxycarbonyl)-modified (Cyoc-modified) mannosamine despite its lower metabolic

• amide [18], carbamate [19], or most recently a urea linkage [20] have been reported. Terminal alkenes are small which is beneficial for being accepted by the enzymes involved in glycan biosynthesis. However, they react only slowly in the DAinv reaction [20]. In contrast, ring-strained alkenes, such as

LCST phase behavior of benzo-21-crown-7 with different alkyl chains

• Yan Deng,
• Xing Li,
• Qiao Zhang,
• Zheng Luo,
• Chengyou Han and
• Shengyi Dong

Beilstein J. Org. Chem. 2019, 15, 437–444, doi:10.3762/bjoc.15.38

• and molecular structures. Results and Discussion Two series of B21C7s, comprising carbamate-based linkers 3a–e and urea-based linkers 5a–e, were designed and synthesized, as shown in Scheme 1 and Scheme 2. All structures were confirmed by NMR spectroscopy and high-resolution mass spectrometry (details

• between the amine groups and isocyanate units (yields, 44.6–76.5%), or between hydroxy groups and isocyanate units (yields, 57.4–84.9%), respectively. We also investigated the role of linkages in LCST behavior by the introduction of urea-based and carbamate-based linkers. The water solubility of the

• ethers with urea-based linkers show higher water solubility (5a–e), compared to crown ethers with carbamate-based linkers (3a–e). As amide groups are more hydrophilic compared with ester groups, it is reasonable that 5a–e show stronger hydration effects and exhibit a larger water-accessible surface area

Tandem copper and photoredox catalysis in photocatalytic alkene difunctionalization reactions

• Nicholas L. Reed,
• Madeline I. Herman,
• Vladimir P. Miltchev and
• Tehshik P. Yoon

Beilstein J. Org. Chem. 2019, 15, 351–356, doi:10.3762/bjoc.15.30

• describe a method for alkene oxyamination and diamination that utilizes simple carbamate and urea groups as nucleophilic heteroatom donors. This method uses a tandem copper–photoredox catalyst system that is operationally convenient. The identity of the terminal oxidant is critical in these studies. Ag(I

• of carbamate 1 (Table 1), a reaction we had previously studied under stoichiometric Cu(II) conditions and found to proceed in good yield using 2.5 mol % 2,4,6-triphenylpyrylium tetrafluoroborate (TPPT, 3) as a photocatalyst and 1.2 equiv of Cu(TFA)2 as a stoichiometric oxidant. We lowered the loading

• tether (15) did not adversely affect the reaction. Intermolecular oxyamination of styrenes is also feasible using these conditions. While simple styrenes polymerize rapidly under these conditions, a range of β-substituted styrenes undergo smooth oxyamination using tert-butyl carbamate as the nucleophilic

Sigmatropic rearrangements of cyclopropenylcarbinol derivatives. Access to diversely substituted alkylidenecyclopropanes

• Guillaume Ernouf,
• Jean-Louis Brayer,
• Christophe Meyer and
• Janine Cossy

Beilstein J. Org. Chem. 2019, 15, 333–350, doi:10.3762/bjoc.15.29

• -disubstitution at C3 on the three-membered ring. Alcohol 25 was readily converted to carbamate 26 by reaction with trichloroacetyl isocyanate followed by cleavage of the trichloroacetyl group by alkaline hydrolysis. Dehydration of carbamate 26 was achieved by treatment with trifluoroacetic anhydride in the

• at 40 °C but could be accelerated by addition of Ti(OiPr)4 (10 mol %) to deliver the corresponding N-Boc- carbamate 36 (81%). The condensation of isocyanate 28 with N-Boc-glycine in the presence of DMAP (Goldschmidt–Wick coupling) [57] provided amide 37 in 70% yield (Scheme 16) [53]. The examination

• ) arising from the [3,3]-sigmatropic rearrangement of cyclopropenylcarbinyl cyanates could also be derivatized into trifluoroacetamides. This transformation was discovered fortuitously when carbamate 49 was treated with an excess of trifluoroacetic anhydride (2 equiv) in the presence of Et3N (3 equiv) to

Silanediol versus chlorosilanol: hydrolyses and hydrogen-bonding catalyses with fenchole-based silanes

• Falco Fox,
• Jörg M. Neudörfl and
• Bernd Goldfuss

Beilstein J. Org. Chem. 2019, 15, 167–186, doi:10.3762/bjoc.15.17

• ion catalyses The N-acyl Mannich reaction of isochinolin (16), which is activated with 2,2,2-trichloroethoxycarbonyl chloride (17, TrocCl) to carbamate 10, and different silyl ketene acetals 11a–d yielding product 12 (Scheme 6) [45][47], is studied. Mattson et al. proposed a mechanism where the

Stereodivergent approach in the protected glycal synthesis of L-vancosamine, L-saccharosamine, L-daunosamine and L-ristosamine involving a ring-closing metathesis step

• Pierre-Antoine Nocquet,
• Aurélie Macé,
• Frédéric Legros,
• Jacques Lebreton,
• Gilles Dujardin,
• Sylvain Collet,
• Arnaud Martel,
• Bertrand Carboni and
• François Carreaux

Beilstein J. Org. Chem. 2018, 14, 2949–2955, doi:10.3762/bjoc.14.274

• speculated that the cyclic vinyl ether derivative I, with the prerequisite configuration of all stereogenic centers of the carbamate-protected glycal of L-vancosamine 1, could be obtained from the alcohol derivative II using an O-vinylation–ring-closing metathesis sequence (Figure 3). Afterwards, the

• diastereoisomer, the carbamate-protected 3-aminoglycal of L-saccharosamine 2, employing the (S)-(−)-methyl lactate as common starting material. The efficiency and generality of this methodology was also demonstrated by a new synthesis of C-3 unbranched amino glycals, L-daunosamine 3 and L-ristosamine 4

• synthesis of the carbamate-protected glycal of L-vancosamine 1 and L-saccharosamine 2 were prepared in two steps by treatment of alcohols with the trichloroacetyl isocyanate reagent (TCA-NCO) followed by basic hydrolysis. The spectroscopic properties of carbamates 17 were identical to those reported in the

Ring-opening metathesis of some strained bicyclic systems; stereocontrolled access to diolefinated saturated heterocycles with multiple stereogenic centers

• Zsanett Benke,
• Melinda Nonn,
• Márton Kardos,
• Santos Fustero and
• Loránd Kiss

Beilstein J. Org. Chem. 2018, 14, 2698–2707, doi:10.3762/bjoc.14.247

• gel (n-hexane/EtOAc). Characterization of the synthesized substances tert-Butyl ((S*)-1-((3R*,5S*)-2-oxo-5-vinyltetrahydrofuran-3-yl)allyl)carbamate ((±)-5). Yellow oil; yield 25%; Rf 0.70 (n-hexane/EtOAc 2:1); 1H NMR (CDCl3, 400 MHz) δ 1.41 (s, 9H, t-Bu), 1.82–1.88 (m, 1H, CH2), 2.40–2.47 (m, 1H

• C14H21NO4: C, 62.90; H, 7.92; N, 5.24; found, C, 62.55; H, 7.58; N, 4.89. tert-Butyl ((R*)-1-((3R*,5S*)-2-oxo-5-vinyltetrahydrofuran-3-yl)allyl)carbamate ((±)-6). Yellow oil; yield 36%; Rf 0.72 (n-hexane/EtOAc 2:1); 1H NMR (CDCl3, 400 MHz) δ 1.47 (s, 9H, t-Bu), 1.94–1.99 (m, 1H, CH2), 2.46–2.51 (m, 1H, CH2

• ]; anal. calcd for C14H21NO4: C, 62.90; H, 7.92; N, 5.24; found, C, 62.59; H, 8.30; N, 4.87. tert-Butyl ((2S*,3R*,4R*)-4-allyl-5-oxo-2-vinyltetrahydrofuran-3-yl)carbamate ((±)-10). Yellow oil; yield 35%; Rf 0.70 (n-hexane/EtOAc 2:1); 1H NMR (CDCl3, 400 MHz) δ 1.48 (s, 9H, t-Bu), 2.42–2.49 (m, 1H, CH2