Amino acid motifs in natural products: synthesis of O-acylated derivatives of (2S,3S)-3-hydroxyleucine

• Oliver Ries,
• Martin Büschleb,
• Markus Granitzka,
• Dietmar Stalke and
• Christian Ducho

Beilstein J. Org. Chem. 2014, 10, 1135–1142, doi:10.3762/bjoc.10.113

• by reductive amination (reactions not displayed), as demonstrated before in our syntheses of simplified muraymycin analogues [21][22]. N-Cbz-protected acid 19 was also used for a methodical study regarding the acylation of the 3-hydroxy group. Therefore, 19 was converted into benzyl ester 23 (70

Molecular architecture with carbohydrate functionalized β-peptides adopting 3₁₄-helical conformation

• Nitin J. Pawar,
• Navdeep S. Sidhu,
• George M. Sheldrick,
• Dilip D. Dhavale and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2014, 10, 948–955, doi:10.3762/bjoc.10.93

• unprotected β-glycopeptides since the equilibrium between hemiacetal and open-chain aldehyde form also does not interfere with the 314-helix secondary structure and allows further functionalization with saccharides, e.g., by reductive amination. Sketch of right-handed β-peptide helix functionalized in every

Phosphinate-containing heterocycles: A mini-review

• Olivier Berger and
• Jean-Luc Montchamp

Beilstein J. Org. Chem. 2014, 10, 732–740, doi:10.3762/bjoc.10.67

• 2 equivalents of cinnamyl alcohol 44 in the presence of 2 mol % of Pd/Xanthpos followed by an esterification using benzyl bromide. Ozonolysis, and reductive amination using excess benzylamine in the presence of sodium cyanoborohydride completed the synthesis. Phosphorines Two phosphorines 47a,b were

• . Tandem Kabacknik–Fields/C–N cross-coupling reaction. Tandem Kabacknik–Fields/C-P cross-coupling reaction. Heterocyclization via amide formation. Cyclization via reductive amination. H-Phosphinate alkylation. Cyclization through intramolecular Michael addition. Double Arbuzov reaction of bis

Concise, stereodivergent and highly stereoselective synthesis of cis- and trans-2-substituted 3-hydroxypiperidines – development of a phosphite-driven cyclodehydration

• Peter H. Huy,
• Julia C. Westphal and
• Ari M. P. Koskinen

Beilstein J. Org. Chem. 2014, 10, 369–383, doi:10.3762/bjoc.10.35

• separation (washing of a basic aqueous solution of the acids 2) of the two equivalents of BnOH formed during the reductive amination (1→I) proved to be challenging: Due to the high amphiphilicity of carboxylate salts of 2, mixtures in water and an organic solvent tend to form three distinct phases separating

Recent applications of the divinylcyclopropane–cycloheptadiene rearrangement in organic synthesis

• Sebastian Krüger and
• Tanja Gaich

Beilstein J. Org. Chem. 2014, 10, 163–193, doi:10.3762/bjoc.10.14

• and reductive amination after Boc-deprotection to yield the desired natural product 131 in only five steps. Perhaps one of the most prominent alkaloid syntheses using a DVCPR was carried out by Fukuyama and coworker [118][119][120] and targeted gelsemine (146, see Scheme 17 and Scheme 18), an alkaloid

Synthesis of five- and six-membered cyclic organic peroxides: Key transformations into peroxide ring-retaining products

• Alexander O. Terent'ev,
• Dmitry A. Borisov,
• Vera A. Vil’ and
• Valery M. Dembitsky

Beilstein J. Org. Chem. 2014, 10, 34–114, doi:10.3762/bjoc.10.6

• 1,2,4-trioxalane 191 was synthesized by reductive amination of adamantane-2-spiro-3’-8’-oxo-1’,2’,4’-trioxaspiro[4.5]-decane 190 (Scheme 52). Ozonide 191 is an example of a combination of two known antiparasitic pharmacophores, viz. a peroxide and an aminoquinoline moiety [296]. Arterolane is a fully

A unified approach to the important protein kinase inhibitor balanol and a proposed analogue

• Tapan Saha,
• Ratnava Maitra and
• Shital K. Chattopadhyay

Beilstein J. Org. Chem. 2013, 9, 2910–2915, doi:10.3762/bjoc.9.327

• preliminary report [62]. Thus, reductive amination of Garner’s aldehyde 17 (Scheme 2) with allylamine produced amine 18 which was N-protected with CbzCl to obtain 19 in an overall yield of 89% over three steps. The oxazolidine ring in compound 19 was then cleaved under acidic conditions and the resulting

Microwave-assisted synthesis of 5,6-dihydroindolo[1,2-a]quinoxaline derivatives through copper-catalyzed intramolecular N-arylation

• Fei Zhao,
• Lei Zhang,
• Hailong Liu,
• Shengbin Zhou and
• Hong Liu

Beilstein J. Org. Chem. 2013, 9, 2463–2469, doi:10.3762/bjoc.9.285

• intramolecular N-arylation with good to excellent yields. Results and Discussion The required cyclization precursors 1, aryl substituted (1H-indol-2-yl)methanamines, were easily prepared by reductive amination of 1H-indole-2-carbaldehydes with 2-haloanilines in good yields (Scheme 1). Initial screening

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

An investigation of the observed, but counter-intuitive, stereoselectivity noted during chiral amine synthesis via N-chiral-ketimines

• Thomas C. Nugent,
• Richard Vaughan Williams,
• Andrei Dragan,
• Alejandro Alvarado Méndez and
• Andrei V. Iosub

Beilstein J. Org. Chem. 2013, 9, 2103–2112, doi:10.3762/bjoc.9.247

• ensuing experimental and computational (DFT) results favor the former, pre-existing, explanation. Keywords: chiral amines; cis/trans isomerization; imine isomerization; imine reduction; reductive amination; Introduction A class of chiral compounds drawing ever more attention is α-chiral amines (chiral

• , nitrogen C–H insertion [10][11][12], hydroamination [13][14][15][16], hydroaminoalkylation [17][18], reductive amination [19][20][21][22][23], and enamine reduction [23][24][25][26][27] are experiencing a renaissance; while imine reduction [23][28][29][30], N-acylenamide reduction [23][24], and carbanion

• most atom-economic reducing agent available. Of further advantage, we were familiar with the phenomenon (mediocre cis/trans N-chiral imine ratios yielding good to excellent amine product diastereomeric ratios) from our previous work with (R)- or (S)-PEA-based reductive amination with hydrogen [54][58

Synthesis and antibacterial activity of monocyclic 3-carboxamide tetramic acids

• Yong-Chul Jeong and
• Mark G. Moloney

Beilstein J. Org. Chem. 2013, 9, 1899–1906, doi:10.3762/bjoc.9.224

• cyclisation of N-acetoacetylamino acid esters leading to 3-acetyltetramates has been reported, which give N–H rather than N-alkyl systems [15][16][17]. Tetramate 7 was obtained from amino acid 6, except that the key intermediate 5 was obtained by reductive amination (Scheme 2) of (R)-citronellal (4), which

Amyloid-β probes: Review of structure–activity and brain-kinetics relationships

• Todd J. Eckroat,
• Abdelrahman S. Mayhoub and
• Sylvie Garneau-Tsodikova

Beilstein J. Org. Chem. 2013, 9, 1012–1044, doi:10.3762/bjoc.9.116

• -iodopyridine (131) to give 132, which was followed by reductive amination and O-demethylation to give 133 (Scheme 9B). Finally, reaction with 2-[2-(2-chloroethoxy)ethoxy]ethanol (134) followed by radiolabeling gave 123a. This compound showed high affinity for Aβ1-42 aggregates (Ki = 0.9 nM), the ability to

Aqueous reductive amination using a dendritic metal catalyst in a dialysis bag

• Jorgen S. Willemsen,
• Jan C. M. van Hest and
• Floris P. J. T. Rutjes

Beilstein J. Org. Chem. 2013, 9, 960–965, doi:10.3762/bjoc.9.110

• metal complex to DAB-Am dendrimers via an adapted asymmetric bipyridine ligand. These dendritic catalysts were applied in the aqueous reductive amination of valine while contained in a dialysis bag. Comparable conversions were observed as for the noncompartmentalized counterparts, albeit with somewhat

• longer reaction times. These results clearly show that the encapsulated catalyst system is suitable to successfully drive a complex reaction mixture with various equilibrium reactions to completion. Keywords: aqueous reductive amination; cascade catalysis; compartmentalization; dendritic catalysts

• examples, we decided to design a metallodendrimer that would show catalytic activity in a cascade process while compartmentalized under aqueous conditions. To this end, an iridium catalyst was selected that was known to be suitable for reductive amination in an aqueous environment. We showed that by

Gold-catalyzed oxycyclization of allenic carbamates: expeditious synthesis of 1,3-oxazin-2-ones

• Benito Alcaide,
• Pedro Almendros,
• M. Teresa Quirós and
• Israel Fernández

Beilstein J. Org. Chem. 2013, 9, 818–826, doi:10.3762/bjoc.9.93

• , alkynylcarbamates 1a–g were prepared through reductive amination of the appropriate aldehyde with propargylamine, followed by Boc2O treatment of the corresponding N-substituted prop-2-yn-1-amine. Alkynylcarbamate 1h was prepared from Garner’s aldehyde following a literature report [56][57]. Alkynylcarbamate 1i was

Multivalent display of the antimicrobial peptides BP100 and BP143

• Imma Güell,
• Rafael Ferre,
• Kasper K. Sørensen,
• Esther Badosa,
• Iteng Ng-Choi,
• Emilio Montesinos,
• Eduard Bardají,
• Lidia Feliu,
• Knud J. Jensen and
• Marta Planas

Beilstein J. Org. Chem. 2012, 8, 2106–2117, doi:10.3762/bjoc.8.237

• , respectively, were prepared by using a standard backbone amide linker (BAL) strategy (Scheme 1). PALdehyde was coupled onto an amino-functionalized TentaGel (TG) resin followed by reductive amination with aminoacetaldehyde dimethyl acetal, which served as a precursor for the C-terminal glycinal residue. Next

• performed with DMF (3 × 1 min), CH2Cl2 (3 × 1 min) and DMF (3 × 1 min). Next a reductive amination was performed by using aminoacetaldehyde dimethyl acetal (10 equiv) and NaBH3CN (10 equiv) suspended in AcOH/DMF (1:99). This suspension was added to the o-BAL-TG resin and the mixture was heated in a

• microwave instrument at 60 °C for 10 min. The resin was washed with DMF (3 × 1 min), CH2Cl2 (3 × 1 min) and dichloroethane (DCE) (3 × 1 min) and the reductive amination step was repeated. Then, Fmoc-Leu-OH (10 equiv) was dissolved in DCE/DMF (10:1), DIPCDI (5 equiv) was added, and after preactivation for 10

Acylsulfonamide safety-catch linker: promise and limitations for solid–phase oligosaccharide synthesis

• Jian Yin,
• Steffen Eller,
• Mayeul Collot and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2012, 8, 2067–2071, doi:10.3762/bjoc.8.232

• revealed during final deprotection serves in the formation of glycoconjugates and glycan microarrays [19]. Synthesis of 10 relied on key intermediates 4 and 6 (Scheme 1). Monobenzylated amine 4 was prepared by reductive amination [20]. An established three-step synthesis starting with hydrocinnamic acid

Automated three-component synthesis of a library of γ-lactams

• Erik Fenster,
• David Hill,
• Oliver Reiser and
• Jeffrey Aubé

Beilstein J. Org. Chem. 2012, 8, 1804–1813, doi:10.3762/bjoc.8.206

• ; maleimide; organocatalysis; parallel synthesis; reductive amination; Introduction In recent years, the rapid access to structurally diverse and complex small molecules has grown in importance within the context of high-throughput screening of biologically relevant targets. The need for such compounds, both

• , aldehydes and amines [12]. The method involved a three-step stepwise sequence involving an organocatalyzed Michael addition, a reductive amination/intramolecular lactamization, and an epimerization step (Scheme 1). It culminated in the preparation of a 43-member library. Although this method permitted

• with the modest enantiomeric enrichment in hand. Combination of three discrete steps into a single-pot process We next turned our attention to combining the initial Michael addition step with the remaining reductive amination/lactamization and epimerization steps. In the original procedure, the

Two-directional synthesis as a tool for diversity-oriented synthesis: Synthesis of alkaloid scaffolds

• Kieron M. G. O’Connell,
• Monica Díaz-Gavilán,
• Warren R. J. D. Galloway and
• David R. Spring

Beilstein J. Org. Chem. 2012, 8, 850–860, doi:10.3762/bjoc.8.95

• effected the desired double reductive amination to give 17 in 30% yield. It is likely that the scope of this sequence could be extended to include indolizidine and quinolizidine scaffolds, and so provide an alternative route to these frameworks, instead of the double Michael addition strategy. The three

Synthesis and characterization of Sant-75 derivatives as Hedgehog-pathway inhibitors

• Chao Che,
• Song Li,
• Bo Yang,
• Shengchang Xin,
• Zhixiong Yu,
• Taofeng Shao,
• Chuanye Tao,
• Shuo Lin and
• Zhen Yang

Beilstein J. Org. Chem. 2012, 8, 841–849, doi:10.3762/bjoc.8.94

•  1. Accordingly, Suzuki coupling of 4-bromopyridine and 3-formylphenylboronic acid afforded biaryl aldehyde 2, which was then subjected to a reductive amination by condensation of aldehyde 2 with N-Boc-cyclohexane-1,4-diamine, followed by reduction with NaBH(OAc)3 to afford secondary amine 3

Chemo-enzymatic modification of poly-N-acetyllactosamine (LacNAc) oligomers and N,N-diacetyllactosamine (LacDiNAc) based on galactose oxidase treatment

• Christiane E. Kupper,
• Ruben R. Rosencrantz,
• Birgit Henßen,
• Helena Pelantová,
• Stephan Thönes,
• Anna Drozdová,
• Vladimir Křen and
• Lothar Elling

Beilstein J. Org. Chem. 2012, 8, 712–725, doi:10.3762/bjoc.8.80

• -aldo product. Further modification of the aldehyde containing glycans, either by chemical conversion or enzymatic elongation, was established. Base-catalysed β-elimination, coupling of biotin–hydrazide with subsequent reduction to the corresponding hydrazine linkage, and coupling by reductive amination

• of poly-LacNAc oligomers was utilised for the reductive amination of 6-aldehyde groups of oxidised poly-LacNAc oligomers (Scheme 4). In this way, chemically branched poly-LacNAc glycans are synthesised that resemble natural, branched poly-LacNAc glycans (I-antigens) of glycoproteins and glycolipids

• coupling of a deprotected poly-LacNAc–linker–NH2 glycan (17), which was synthesised as described previously [45][55]. On an analytical scale, a heptasaccharide–linker–NH2 glycoconjugate 17 was coupled to the aldehyde groups of 3a or 10a by reductive amination leading to the chemically branched poly-LacNAc

2-Allylphenyl glycosides as complementary building blocks for oligosaccharide and glycoconjugate synthesis

• Hemali D. Premathilake and
• Alexei V. Demchenko

Beilstein J. Org. Chem. 2012, 8, 597–605, doi:10.3762/bjoc.8.66

• can be reverted as needed (active–latent strategy). Direct conjugation of the AP moiety to biomolecules, monolayers, arrays, etc., should be possible by executing thiol–ene chemistry [43], ozonolysis/reductive amination [44][45][46], or other ligation protocols [47][48]. Experimental General remarks

Synthesis and biological evaluation of nojirimycin- and pyrrolidine-based trehalase inhibitors

• Davide Bini,
• Francesca Cardona,
• Matilde Forcella,
• Camilla Parmeggiani,
• Paolo Parenti,
• Francesco Nicotra and
• Laura Cipolla

Beilstein J. Org. Chem. 2012, 8, 514–521, doi:10.3762/bjoc.8.58

• , deprotection of intermediate 28 afforded monosubstituted urea 16 in only 58% purity. In addition, pyrrolidines 20 and 21 were synthesized in a few steps from nitrone 30 [23]. Catalytic hydrogenation over Pd/C followed by reductive amination in the presence of octanal and NaBH3CN afforded compound 20 in 33

Coupled chemo(enzymatic) reactions in continuous flow

• Ruslan Yuryev,
• Simon Strompen and
• Andreas Liese

Beilstein J. Org. Chem. 2011, 7, 1449–1467, doi:10.3762/bjoc.7.169

• using a coupled parallel enzymatic system [22]. Here, L-leucine dehydrogenase was used for the reductive amination of α-ketoisocaproate (1) to the amino acid 3. The required cofactor NADH was regenerated in a coupled parallel reaction by oxidation of formate (2) catalyzed by formate dehydrogenase

• tested in the continuous simultaneous synthesis of gluconic acid (9) and glutamic acid (8) by coupling the NADP+-dependent glucose (7) oxidation catalyzed by glucose oxidase with the reductive amination of α-ketoglutaric acid (6) catalyzed by glutamate dehydrogenase (Scheme 3). When the process was

Amine-linked diglycosides: Synthesis facilitated by the enhanced reactivity of allylic electrophiles, and glycosidase inhibition assays

• Ian Cumpstey,
• Jens Frigell,
• Elias Pershagen,
• Tashfeen Akhtar,
• Elena Moreno-Clavijo,
• Inmaculada Robina,
• Dominic S. Alonzi and
• Terry D. Butters

Beilstein J. Org. Chem. 2011, 7, 1115–1123, doi:10.3762/bjoc.7.128

• aminated amine-linked sec–sec structures by aziridine-opening reactions (ionic liquid, 120 °C) [9]. Primary–sec amine-linked structures have been synthesised by Thiem et al., through a reductive amination strategy [10][11]. In contrast, related structures containing an amine linkage between a carbohydrate

Reductive amination with zinc powder in aqueous media

• Giovanni B. Giovenzana,
• Daniela Imperio,
• Andrea Penoni and
• Giovanni Palmisano

Beilstein J. Org. Chem. 2011, 7, 1095–1099, doi:10.3762/bjoc.7.125

• , Via Valleggio 11, I-22100 Como, Italy; Fax: +39-(0)31-2386449, Tel: +39-(0)31-2386234 10.3762/bjoc.7.125 Abstract Zinc powder in aqueous alkaline media was employed to perform reductive amination of aldehydes with primary amines. The corresponding secondary amines were obtained in good yields along

• with minor amounts of hydrodimerization byproducts. The protocol is a green alternative to the use of complex hydrides in chlorinated or highly flammable solvents. Keywords: aldehydes; amines; reductive amination; water; zinc; Introduction Reductive amination is the name usually employed to indicate

• ], Zn(BH4)2/ZnCl2 [10], NaBH4/Mg(ClO4)2 [11], electrochemistry [12], 1,4-dihydropyridines [13][14], Ti(OiPr)4-PMHS [15], NaBH4-CoCl2 [16], iPrOH/RuCl(PPh3)2 [17], BH3·Me2S [18], PhSiH3-Bu2SnCl2 [19], and Zn/HCOONH4 [20]. Although the choice of reagents for reductive amination is quite large, a closer