Synthesis of (−)-halichonic acid and (−)-halichonic acid B

• Keith P. Reber and
• Emma L. Niner

Beilstein J. Org. Chem. 2022, 18, 1629–1635, doi:10.3762/bjoc.18.174

• aminobisabolene sesquiterpenoid halichonic acid ((+)-1) from the sponge Halichondra sp. (Figure 1) [4]. This amino acid natural product features a rigid 3-azabicyclo[3.3.1]nonane ring system containing four stereogenic centers within the piperidine ring. In 2021, the same group re-isolated (+)-1 from the sponge

• Axinyssa sp. along with the structurally related compound halichonic acid B ((+)-2) [5]. Structurally, (+)-2 is a pipecolic acid derivative containing a cyclohexenyl ring as a substituent group. This compound also features four stereogenic centers (three of which are located within the piperidine ring) and

Solid-phase total synthesis and structural confirmation of antimicrobial longicatenamide A

• Takumi Matsumoto,
• Takefumi Kuranaga,
• Yuto Taniguchi,
• Weicheng Wang and
• Hideaki Kakeya

Beilstein J. Org. Chem. 2022, 18, 1560–1566, doi:10.3762/bjoc.18.166

• synthesized the necessary building blocks, we turned our attention to construct resin-bound peptide 5 (Scheme 4). The assembly of this hexapeptide started with the loading of Fmoc-ᴅ-Trp(Boc)-OH (6) onto 2-chlorotrityl resin with iPr2NEt, which was followed by piperidine treatment to liberate resin-bound amine

• 29. Then, five rounds of DIC/Oxyma-mediated amidation [22] and Nα-deprotection with piperidine led to resin-bound peptide 5. Treatment of 5 with TFA/CH2Cl2 1:99 released 30 into the solution without unmasking the acid-labile protecting groups of the side chains. Subsequently, peptide 30 was cyclized

Vicinal ketoesters – key intermediates in the total synthesis of natural products

• Marc Paul Beller and
• Ulrich Koert

Beilstein J. Org. Chem. 2022, 18, 1236–1248, doi:10.3762/bjoc.18.129

• ]. The major trans-isomer 73 was further converted to the natural products corynoxine and rychnophylline. The minor cis-isomer 74 was used in an intramolecular Tsuji–Trost reaction, where the ketoester served as a nucleophile, which build up the piperidine ring and selectively set the desired cis

Cholyl 1,3,4-oxadiazole hybrid compounds: design, synthesis and antimicrobial assessment

• Anas J. Rasras,
• Mohamed El-Naggar,
• Nesreen A. Safwat and
• Raed A. Al-Qawasmeh

Beilstein J. Org. Chem. 2022, 18, 631–638, doi:10.3762/bjoc.18.63

• were obtained from piperidine and pyrrolidine, respectively, as secondary cyclic amine component (Figure 2). The structures of the newly synthesized compounds were confirmed on the basis of their spectral data in particular nuclear magnetic resonance (NMR) and mass spectrometry (MS) techniques. The 1H

Heteroleptic metallosupramolecular aggregates/complexation for supramolecular catalysis

• Prodip Howlader and
• Michael Schmittel

Beilstein J. Org. Chem. 2022, 18, 597–630, doi:10.3762/bjoc.18.62

Synthesis of piperidine and pyrrolidine derivatives by electroreductive cyclization of imine with terminal dihaloalkanes in a flow microreactor

• Yuki Naito,
• Naoki Shida and
• Mahito Atobe

Beilstein J. Org. Chem. 2022, 18, 350–359, doi:10.3762/bjoc.18.39

• Yuki Naito Naoki Shida Mahito Atobe Graduate School of Science and Engineering, Yokohama National University, Yokohama, Kanagawa 240-8501, Japan 10.3762/bjoc.18.39 Abstract We have successfully synthesized piperidine and pyrrolidine derivatives by electroreductive cyclization using readily

• . Furthermore, piperidine and pyrrolidine derivatives could be obtained on preparative scale by continuous electrolysis for approximately 1 hour. Keywords: electrochemical synthesis; electrocyclization; flow microreactor; heterocyclic amines; imine; Introduction Heterocycles are a very important class of

• compounds and make up more than half of all known organic chemicals [1]. Among them, heterocyclic amines, particularly pyrrolidine and piperidine derivatives, have attracted considerable attention because these are important structural motifs in a wide variety of applications including pharmaceuticals

Regioselective synthesis of methyl 5-(N-Boc-cycloaminyl)-1,2-oxazole-4-carboxylates as new amino acid-like building blocks

• Jolita Bruzgulienė,
• Greta Račkauskienė,
• Aurimas Bieliauskas,
• Vaida Milišiūnaitė,
• Miglė Dagilienė,
• Gita Matulevičiūtė,
• Vytas Martynaitis,
• Sonata Krikštolaitytė,
• Frank A. Sløk and
• Algirdas Šačkus

Beilstein J. Org. Chem. 2022, 18, 102–109, doi:10.3762/bjoc.18.11

• blocks was developed. Regioisomeric methyl 5-(N-Boc-cycloaminyl)-1,2-oxazole-4-carboxylates were prepared by the reaction of β-enamino ketoesters (including azetidine, pyrrolidine or piperidine enamines) with hydroxylamine hydrochloride. Unambiguous structural assignments were based on chiral HPLC

• characteristic signals of the 1,2-oxazole ring skeleton carbons at δ 108.3 (C-4), 150.2 (C-3), and 179.5 (C-5) ppm. The 15N NMR spectrum of 4h exhibited characteristic resonances of nitrogen atoms at δ −294.6 (piperidine) and δ −3.1 (1,2-oxazole) ppm, respectively. Next, we studied the reaction of compounds 4b

Recent advances and perspectives in ruthenium-catalyzed cyanation reactions

• Thaipparambil Aneeja,
• Cheriya Mukkolakkal Abdulla Afsina,
• Padinjare Veetil Saranya and
• Gopinathan Anilkumar

Beilstein J. Org. Chem. 2022, 18, 37–52, doi:10.3762/bjoc.18.4

• such as piperidine, tetrahydroisoquinoline derivatives, and pyrrolidine were also tolerated well in this reaction. The use of the non-toxic and inexpensive acetone cyanohydrin makes this method more advantageous compared to the known methods. 2 Cyanation of arenes and heteroarenes 2.1 Cyanation of

First total synthesis of hoshinoamide A

• Haipin Zhou,
• Zihan Rui,
• Yiming Yang,
• Shengtao Xu,
• Yutian Shao and
• Long Liu

Beilstein J. Org. Chem. 2021, 17, 2924–2931, doi:10.3762/bjoc.17.201

• -OH (4 equiv), HATU/coupling reagent (4 equiv) and DIPEA (8 equiv) in DMF (20 mL). The coupling mixture was filtered and the resin was washed with CH2Cl2 (10 mL × 5) and CH3OH (10 mL × 5). General procedures for deprotection of Fmoc: The loaded resin was treated with a solution of 20 vol % piperidine

• MeOH (3 × 20 mL) and DCM (3 × 20 mL). The unreacted resin was capped with MeOH in a mixture of MeOH/DIPEA/DCM (1:2:7, 10 mL) for 3 h. The resin-bound peptide was added to a mixture of 20% piperidine in DMF (20 mL), and the mixture was shaken for 30 minutes. Then the mixture was filtered, and the resin

• mL) and DCM (3 × 20 mL) to afford the resin-bound dipeptide. The resin-bound dipeptide was added to a mixture of 20% piperidine in DMF (20 mL), and the mixture was shaken for 30 minutes. Then the mixture was filtered, and the resin was washed with MeOH (3 × 20 mL) and DCM (3 × 20 mL). Fmoc-Val-OH

Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones

• Robin Klintworth,
• Garreth L. Morgans,
• Stefania M. Scalzullo,
• Charles B. de Koning,
• Willem A. L. van Otterlo and
• Joseph P. Michael

Beilstein J. Org. Chem. 2021, 17, 2543–2552, doi:10.3762/bjoc.17.170

• with the microwave-assisted synthesis of 2,3-dihydro-1H-pyrrolizines from pyrrolidine-based enaminones suggested that the technique might also be suitable for preparing 5,6,7,8-tetrahydroindolizine analogues from the corresponding piperidine systems. In a preliminary investigation we prepared three

• tetrahydroindolizine formation from the piperidine-containing enaminone, we speculated that a simple polar protic solvent might be sufficiently “acidic” for the necessary E/Z equilibration and cyclization of 25a, even though this solvent was unsuitable for the cyclization of the pyrrolidine enaminones (cf. Table 1

Copper-catalyzed monoselective C–H amination of ferrocenes with alkylamines

• Zhen-Sheng Jia,
• Qiang Yue,
• Ya Li,
• Xue-Tao Xu,
• Kun Zhang and
• Bing-Feng Shi

Beilstein J. Org. Chem. 2021, 17, 2488–2495, doi:10.3762/bjoc.17.165

• ][58]. We then explored the scope of multifarious amines. As displayed in Scheme 3, a range of cyclic amines, such as morpholine 4a,b, piperazine 4c, piperidine 4d–j and thiomorpholine 4l,m, reacted smoothly to give the amination products in 23% to 85% yields. A variety of synthetically useful

Advances in mercury(II)-salt-mediated cyclization reactions of unsaturated bonds

• Sumana Mandal,
• Raju D. Chaudhari and
• Goutam Biswas

Beilstein J. Org. Chem. 2021, 17, 2348–2376, doi:10.3762/bjoc.17.153

• piperidine derivatives were also synthesized by Hg(II)-salt-induced cyclization. N-Isopropyl-1-aminohex-4-ene (23) on treatment with 1 equiv HgCl2 followed by reduction with NaBH4 yielded pyrrolidine 24 and piperidine derivative 25 in the ratio of 7:3 [50]. N-Methylaniline derivative 26 undergoes cyclization

• . Synthesis of β-ᴅ-arabinose derivative 18. Hg(OAc)2-mediated synthesis of tetrahydrofuran derivatives. Synthesis of Hg(TFA)2-mediated bicyclic nucleoside derivative. Synthesis of pyrrolidine and piperidine derivatives. HgCl2-mediated synthesis of diastereomeric pyrrolidine derivatives. HgCl2-mediated

Progress and challenges in the synthesis of sequence controlled polysaccharides

• Giulio Fittolani,
• Theodore Tyrikos-Ergas,
• Denisa Vargová,
• Manishkumar A. Chaube and
• Martina Delbianco

Beilstein J. Org. Chem. 2021, 17, 1981–2025, doi:10.3762/bjoc.17.129

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

• hydroquinolinone, chromene, piperidine, peptide, lipid, and glycoside moieties (Scheme 2). Bojanowski and co-workers developed a methodology to synthetize 3,4-dihydrocoumarins 10 through a decarboxylative and dearomatizative cascade reaction [33]. This reaction was carried out using coumarin-3-carboxylic acids 8

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• fluorination of pyridine or 2-fluoropyridine in anhydrous hydrogen fluoride [17][18] (Scheme 2). Not surprisingly, 1-1 did not become a popular reagent. In 1967, Banks et al. reported reactions of 1-1 with piperidine and triphenylphosphine, -arsine, and -stibine (Scheme 3, entries 1 and 2) [19]. The former

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

• . Moreover, TMS-substituted alkyne was suitable for this Huisgen reaction to achieve the desired triazole product. Next, some triazene scaffolds, such as dimethylamino-, pyrrolidine-, piperidine-, morpholine-, and piperazine-derived triazenes were screened. Aryl azides containing Br, I, Me, and MeO as well

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• ). Asymmetric synthesis of piperidines The six-membered nitrogen-containing rings are the most common heterocycles among natural products and also synthetic pharmaceutical drugs [107][108]. For this reason, the piperidine unit has attracted great attention among organic chemists [109]. Due to that, a large

• reaction intermediate that was not isolated. Treatment of 115 with potassium hexamethyldisilazide (KHMDS) led to the sulfinyl piperidine derivative 116, and final deprotection under acidic conditions produced enantioenriched 2-allylpiperidine (117) as its hydrochloride (Scheme 32) [121]. Compound 117 has

• led to (−)-pelletierine (112) alkaloid. Yus and co-workers developed the synthesis of the piperidine alkaloids (+)-dihydropinidine (122a), (+)-isosolenopsin (122b), (+)-isosolenopsin A (122c) and (2R,6R)-6-methylpipecolic acid hydrochloride by oxidation of the aromatic ring of (2R,6R)-2-methyl-6

Application of the Meerwein reaction of 1,4-benzoquinone to a metal-free synthesis of benzofuropyridine analogues

• Rashmi Singh,
• Tomas Horsten,
• Rashmi Prakash,
• Swapan Dey and
• Wim Dehaen

Beilstein J. Org. Chem. 2021, 17, 977–982, doi:10.3762/bjoc.17.79

• presence of a catalytic amount of piperidine afforded pyridopsoralen 22 in 46% yield. Analogously, pyridopsoralen 23 was prepared from 16 by Knoevenagel condensation with diethyl malonate and subsequent lactonization with 62% yield (Scheme 4) [13]. To the best of our understanding, the scaffolds 21–23 are

Enhanced target cell specificity and uptake of lipid nanoparticles using RNA aptamers and peptides

• Roslyn M. Ray,
• Anders Højgaard Hansen,
• Maria Taskova,
• Bernhard Jandl,
• Jonas Hansen,
• Citra Soemardy,
• Kevin V. Morris and
• Kira Astakhova

Beilstein J. Org. Chem. 2021, 17, 891–907, doi:10.3762/bjoc.17.75

• columns. Initially, fluorenylmethyloxycarbonyl (Fmoc) group removal from the Rink linker was achieved by applying 20% piperidine in DMF (2 × 30 min). Preactivation of Fmoc amino acid (4 equiv) prior each coupling was performed with 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide

• deprotection was achieved via 20% piperidine in DMF (1 × 2 min and 1 × 18 min) to prepare the resin for the next coupling step. The resin was washed three times with each solvent in the given order DMF, DCM, and DMF after every reaction step. Peptide sequences T7: H-HAIYPRH-NH2 Modified T7: dipalmitoyl-Dap

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• pyridopyrimidines 94 utilizing a piperidine-catalyzed microwave-assisted four-component reaction by employing 1,1-dimethylthio-2-nitroethylene (91), 1,3-propanediamine (92), phenylsulfonyl acetonitrile 93 and aldehyde 5 in ethanol as solvent (Scheme 34). The crucial role of time was realized when the yield of the

Amino- and polyaminophthalazin-1(2H)-ones: synthesis, coordination properties, and biological activity

• Zbigniew Malinowski,
• Emilia Fornal,
• Agata Sumara,
• Renata Kontek,
• Karol Bukowski,
• Beata Pasternak,
• Dariusz Sroczyński,
• Joachim Kusz,
• Magdalena Małecka and
• Monika Nowak

Beilstein J. Org. Chem. 2021, 17, 558–568, doi:10.3762/bjoc.17.50

• . As can be seen from Scheme 2 the yields of the amination products 5 and 6 were dependent on the nature of the amine as well as on the used phthalazinone. Efficient results of coupling were received using, inter alia, cyclic, aromatic or benzylamines. The reaction of 3a with piperidine gave a higher

Synthesis and physicochemical evaluation of fluorinated lipopeptide precursors of ligands for microbubble targeting

• Masayori Hagimori,
• Estefanía E. Mendoza-Ortega and
• Marie Pierre Krafft

Beilstein J. Org. Chem. 2021, 17, 511–518, doi:10.3762/bjoc.17.45

• ), piperidine, acetic anhydride, trifluoroacetic acid (TFA), triisopropylsilane (TIS), Rink Amide AM resin (4-(2’,4’-dimethoxyphenyl-Fmoc-aminomethyl)phenoxyacetamido-aminomethyl resin, 100–200 mesh), and Tube-O-DIALYZER™ mini dialysis system (MWCO 1K) from Merck (Darmstadt, Germany). 1,2

• mL column was suspended in 5 mL of DMF and swollen overnight. After washing with DMF (3 × 2 mL), the Fmoc groups of the Rink amide AM resin were activated with 20% of piperidine in DMF (2 mL) for 20 min. After washing with DMF (3 × 2 mL), Fmoc-Ser(t-Bu)-OH (3 equiv) as the first Fmoc-amino acid and

• terminal amino acid, the Fmoc groups of Fmoc-Lys(Fmoc)-OH were activated with 2 × 20% of piperidine in DMF (2 mL) for 20 min, and the coupling reaction with perfluoroalkylated acids (3 equiv) or alkyl acid (3 equiv) was performed 3 times with HBTU/HOBT/DIPEA (6 equiv/6 equiv/12 equiv) for 3 h. After

Synthetic strategies of phosphonodepsipeptides

• Jiaxi Xu

Beilstein J. Org. Chem. 2021, 17, 461–484, doi:10.3762/bjoc.17.41

• chlorination. After the treatment of compound 39 with piperidine, the N-terminal free dipeptide was obtained and acylated with hexanedioic anhydride to afford the designed hapten 40 (Scheme 7) [11]. Phosphonodepsioctapeptide 41 was prepared as a variation of the partial sequence of a gene product of erb B-2

• hydrogenolysis and reaction with Fmoc-OSu, the N-protected phosphonodepsipeptide 145 was transformed to the N-Fmoc-protected phosphonodepsidipeptide 147, which was then coupled with the resin-loaded Cys(Trt)-NH-resin 148. The resin-loaded tripeptide 149 was deprotected with piperidine, coupled with Fmoc-Tyr(Ot

• -Bu) 150, deprotected again with piperidine, and cleaved with TFA and trapping agents. The free phosphonodepsipeptide 151 was obtained in 45% yield after HPLC purification (Scheme 25) [38]. A general and high yielding synthesis of phosphonodepsidipeptides 152 was realized via a Mitsunobu reaction of

Synthesis of trifluoromethyl ketones by nucleophilic trifluoromethylation of esters under a fluoroform/KHMDS/triglyme system

• Yamato Fujihira,
• Yumeng Liang,
• Makoto Ono,
• Kazuki Hirano,
• Takumi Kagawa and
• Norio Shibata

Beilstein J. Org. Chem. 2021, 17, 431–438, doi:10.3762/bjoc.17.39

• common nitrogen-containing compounds such as pyridine, pyrazine, 1H-pyrazole, 1H-indole, 1-methyl-1H-indole, piperidine, and piperazine were subjected to screening. Pyridine and piperidine slightly hamper the reaction of 1g (Table 2, entries 2 and 7, 80–82%). Other nitrogen-containing compounds have more

Supramolecular polymerization of sulfated dendritic peptide amphiphiles into multivalent L-selectin binders

• David Straßburger,
• Svenja Herziger,
• Katharina Huth,
• Moritz Urschbach,
• Rainer Haag and
• Pol Besenius

Beilstein J. Org. Chem. 2021, 17, 97–104, doi:10.3762/bjoc.17.10

• , HOAt, NMM, DMF, 0 °C to rt, 15 h, 93%; iv) SPPS using HBTU, HOBt, DIPEA for coupling (HATU for BTA coupling), 20 vol % piperidine in DMF for Fmoc cleavage, DCM/TFA/TIS 20:20:1 (v/v/v) for final cleavage, 68%; v) azidoacetic acid NHS ester, NMM, DMF, rt, 4 h, 81%; vi) 4, PyBOP, HOAt, NMM, DMF, 0 °C to