Articulated rods – a novel class of molecular rods based on oligospiroketals (OSK)

• Pablo Wessig,
• Roswitha Merkel and
• Peter Müller

Beilstein J. Org. Chem. 2015, 11, 74–84, doi:10.3762/bjoc.11.11

• terminal or lateral positions of the rods. Building blocks with lateral SEGs are called sleeves. In Figure 1 a typical sleeve D (cyan) as well as other typical building blocks of OSK rods are depicted, such as pentaerythritol C (red), cyclohexane-1,4-dione E (green), and piperidine-4-ones B (blue). An OSK

• defined a 1,2,3-triazole containing linkage between two piperidine rings as the flexible joint F, which should be easily accessible by copper-catalyzed cycloaddition between an azide G and a terminal alkyne H (CuAAC, “Click” reaction) [16]. Primary alcohols I serve as “protected” azides accessible by

• modified Appel reaction [17]. The alkynes H can be protected by silylation (J) because only primary alkynes react in the CuAAC (Figure 3). The synthesis commences with 4-hydroxypiperidine (1), which was converted to piperidine-4-one 3 bearing a protected alkyne moiety as well as to piperidin-4-one 5 with a

Enantioselective synthesis of polyhydroxyindolizidinone and quinolizidinone derivatives from a common precursor

• Nemai Saha and
• Shital K. Chattopadhyay

Beilstein J. Org. Chem. 2014, 10, 3104–3110, doi:10.3762/bjoc.10.327

• -piperidine derivative 7 (Scheme 1) in very good yield. The 4-OH group in compound 7 was then protected as its TBDMS ether (8) wherein the use of TBS triflate was essential as the more conventional TBSCl was found to be ineffective. Treatment of the free amino group in 8 with neat acrylic acid provided the

The Shono-type electroorganic oxidation of unfunctionalised amides. Carbon–carbon bond formation via electrogenerated N-acyliminium ions

• Alan M. Jones and
• Craig E. Banks

Beilstein J. Org. Chem. 2014, 10, 3056–3072, doi:10.3762/bjoc.10.323

• functionalise a pyrrolidine or piperidine carbamate [86][87]. A lithium perchlorate–nitromethane system was used to prepare electrochemically azanucleoside derivatives [88]. Unactivated prolinol derivatives underwent anodic oxidation to generate N-acyliminium ions that were intercepted by nucleophilic bases

Formal total syntheses of classic natural product target molecules via palladium-catalyzed enantioselective alkylation

• Yiyang Liu,
• Marc Liniger,
• Ryan M. McFadden,
• Jenny L. Roizen,
• Jacquie Malette,
• Corey M. Reeves,
• Douglas C. Behenna,
• Masaki Seto,
• Jimin Kim,
• Justin T. Mohr,
• Scott C. Virgil and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2014, 10, 2501–2512, doi:10.3762/bjoc.10.261

• enantioselective total synthesis of quebrachamine (Scheme 12) [92]. In their planning, disconnection at the macrocycle led to amide 52, which was prepared from 3,3-disubstituted piperidine 53. The all-carbon quaternary stereocenter in 53 was installed by double alkylation of lactam 55, using an auxiliary to

• furnished N-boc piperidine-alcohol (+)-53 [84], thus intercepting an intermediate in Amat’s synthesis of quebrachamine. G) Vincadifformine Vincadifformine (59) was isolated in both enantioenriched and racemic forms from the leaves and roots of Rhazya stricta in 1963 [93]. Not only is it a representative

Synthesis of aromatic glycoconjugates. Building blocks for the construction of combinatorial glycopeptide libraries

• Markus Nörrlinger and
• Thomas Ziegler

Beilstein J. Org. Chem. 2014, 10, 2453–2460, doi:10.3762/bjoc.10.256

• % piperidine in DMF at room temperature for 3.5 h gave crude aminomethyl compounds 16 and 19 which were used for the next step without further purification. Final coupling of 15 with 16 and 18 with 19 using HBTU, 1-hydroxybenzotriazole (HOBt) and diisopropylethylamine (DIPEA) in DMF as the condenation agent

• gave non-glycosylated fully protected dipeptides 17 and 20 in 73% and 88% yield, respectively (Scheme 2). Likewise, the Fmoc protecting groups in glucosylated building blocks 13a and 14a were first removed with piperidine in DMF to give crude aminomethyl derivates 21 and 23. Next, the latter were

Synthesis of novel conjugates of a saccharide, amino acids, nucleobase and the evaluation of their cell compatibility

• Dan Yuan,
• Xuewen Du,
• Junfeng Shi,
• Ning Zhou,
• Abdulgader Ahmed Baoum and
• Bing Xu

Beilstein J. Org. Chem. 2014, 10, 2406–2413, doi:10.3762/bjoc.10.250

• -Asp (20). After loading the first amino acid (Fmoc-Asp(Ot-Bu)-OH) on the 2-chlorotrityl chloride resin, we blocked the resin by dichloromethane (DCM)/methanol (MeOH)/N,N-diisopropylethylamine (DIEA) (8:1.5:0.5), next removed the Fmoc protecting group by 20% piperidine in N,N-dimethylformamide (DMF

Chiral phosphines in nucleophilic organocatalysis

• Yumei Xiao,
• Zhanhu Sun,
• Hongchao Guo and
• Ohyun Kwon

Beilstein J. Org. Chem. 2014, 10, 2089–2121, doi:10.3762/bjoc.10.218

• chiral cyclic phosphine B1 (Scheme 43) [84]. In the presence of 5 mol % of B1, asymmetric [4 + 2] annulations of allenoates with a broad range of aromatic N-tosylimines worked efficiently in dichloromethane at room temperature to give an array of chiral piperidine derivatives in good to excellent

• stereoselectivities (up to 99% ee, up to 99:1 dr) and moderate to excellent yields (42–99%). The piperidine products could be transformed conveniently into biologically important heterocyclic compounds. For example, with this asymmetric [4 + 2] annulation as the key step, using indole-2-carboxaldehyde as the starting

• , both aryl and alkyl. The addition of a Brønsted acid to the reaction system slightly improved the yields and diastereocontrol. In addition, the resulting tetrahydropyridines could be transformed to more complex dihydroxylated piperidine derivatives. At almost the same time, an intramolecular variant of

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• a secondary amine (i.e., dimethylamine [49][50], diethylamine [51][52], N-methylbenzylamine [49], pyrrolidine [53][54], or piperidine [55][56]) at temperatures ranging from 60 °C to 100 °C afforded the corresponding 5-(alkylaminomethyl)pyrimidine nucleosides 2 (Scheme 2). Compounds 2 served as

Photoswitchable precision glycooligomers and their lectin binding

• Daniela Ponader,
• Sinaida Igde,
• Marko Wehle,
• Katharina Märker,
• Mark Santer,
• David Bléger and
• Laura Hartmann

Beilstein J. Org. Chem. 2014, 10, 1603–1612, doi:10.3762/bjoc.10.166

• Fmoc protecting group was cleaved by treatment with 25% piperidine in DMF three times for 5, 10 and 15 minutes. After complete removal of the Fmoc protecting group, the second building block (AZO or EDS) was coupled following the same reaction conditions. After repetition of the coupling/deprotection

• hours. After that, the resin was washed with a 23 mM solution of sodium diethyl dithiocarbamate in DMF, water, DMF and DCM. Fmoc cleavage: The Fmoc protecting group was cleaved by the addition of a solution of 25% piperidine in DMF three times for 5, 10 and 15 minutes, respectively. This was followed by

C–H-Functionalization logic guides the synthesis of a carbacyclopamine analog

• Sebastian Rabe,
• Johann Moschner,
• Marina Bantzi,
• Philipp Heretsch and
• Athanassios Giannis

Beilstein J. Org. Chem. 2014, 10, 1564–1569, doi:10.3762/bjoc.10.161

• application in the rational design of new hedgehog inhibitors based on lead structure 2. Future work will focus on the synthesis of carbacyclopamine analogs with a piperidine F-ring and their biological investigation. Structures of cyclopamine (1) and carbacyclopamine analog 2. Retrosynthetic analysis of

Orthogonal dual thiol–chloroacetyl and thiol–ene couplings for the sequential one-pot assembly of heteroglycoclusters

• Michele Fiore,
• Gour Chand Daskhan,
• Baptiste Thomas and
• Olivier Renaudet

Beilstein J. Org. Chem. 2014, 10, 1557–1563, doi:10.3762/bjoc.10.160

• resin loading, 3 equiv of Fmoc-protected amino acid activated in situ with 3 equiv of PyBOP and 6 equiv of DIPEA in DMF (10 mL/g resin) for 30 min. Fmoc protecting groups were removed by treatment with a piperidine/DMF solution 1:4 (10 mL/g resin) for 10 min. Synthetic linear peptides were recovered

Efficient routes toward the synthesis of the D-rhamno-trisaccharide related to the A-band polysaccharide of Pseudomonas aeruginosa

• Aritra Chaudhury,
• Sajal K. Maity and
• Rina Ghosh

Beilstein J. Org. Chem. 2014, 10, 1488–1494, doi:10.3762/bjoc.10.153

• would have similar reactivity towards glycosylative activation. Hence, a preactivation-based glycosylation protocol was devised for the first step leading to the disaccharide 11 using 1-benzenesulfinyl piperidine–triflic anhydride (BSP–Tf2O) [46]. The subsequent step was carried out using NIS–TMSOTf to

Design, automated synthesis and immunological evaluation of NOD2-ligand–antigen conjugates

• Marian M. J. H. P. Willems,
• Gijs G. Zom,
• Nico Meeuwenoord,
• Ferry A. Ossendorp,
• Herman S. Overkleeft,
• Gijsbert A. van der Marel,
• Jeroen D. C. Codée and
• Dmitri V. Filippov

Beilstein J. Org. Chem. 2014, 10, 1445–1453, doi:10.3762/bjoc.10.148

• the antigenic peptide was protected with the methyl trityl (Mtt) protective group, allowing the modification of both the N- or C-terminal end at the final stage of the synthesis. In a standard elongation cycle using HCTU as a coupling reagent, acetic anhydride as capping reagent and piperidine to

• , 80%; 2) Fmoc-Glu-(OH)-OAllyl, HATU, DIPEA, DMF, 57%; i) Pd(PPh3)4, Bu3SnH, AcOH, DMF, 72%; j) 60% AcOH, H2O, neopentylglycol, 88%; k) Ac2O, pyridine; l) 20% TFA, DCM, 82% (2 steps); m) NH4OH, MeOH, 87%. a) 20% piperidine, NMP; b) Fmoc SPPS DEVA5K; c) Fmoc-D-isoGln-OH, HCTU, DIPEA, NMP; d) Fmoc-L-Ala

Streptopyridines, volatile pyridine alkaloids produced by Streptomyces sp. FORM5

• Ulrike Groenhagen,
• Michael Maczka,
• Jeroen S. Dickschat and
• Stefan Schulz

Beilstein J. Org. Chem. 2014, 10, 1421–1432, doi:10.3762/bjoc.10.146

• . FORM5 are structurally related to known secondary metabolites by Streptomyces. The piperidine derivatives 2-((1E,3E)-1,3-pentadienyl)piperidine (20) and 2-((1E,3E)-1,3-pentadienyl)piperidin-4-ol (SS20846A, 21, Figure 5) have been reported from other streptomycetes [8][22][23]. They constitute

• ). Although the compounds were not isolated, the mass spectral data and the previous reports of this class of compounds from Streptomyces led us to conclude that these compounds are indeed streptazolin (5, molecular mass 207) and 2-(penta-1,3-dien-1-yl)piperidine (20, molecular mass 151, mass spectra and high

• [24] and cannot be formed in piperidine 20 because of the adjacent double bond. The 3-pentenyl side chain is also supported by a small ion series at m/z 94 and 108 and present in streptopyridine E (8) and streptenols A (28) and B, biosynthetic precursors of this compound family (see below). Another

Automated solid-phase peptide synthesis to obtain therapeutic peptides

• Veronika Mäde,
• Sylvia Els-Heindl and
• Annette G. Beck-Sickinger

Beilstein J. Org. Chem. 2014, 10, 1197–1212, doi:10.3762/bjoc.10.118

• for tumor therapy as well. Here, ortho-carbaboranyl propionic acid (Cpa) (Figure 5) was coupled to lysine side chains on a resin-bound peptide in a manual step. An alternative Fmoc-cleavage procedure for the following coupling steps assured the stability of the piperidine-labile carbaborane moiety

• , Aa: amino acid. Fmoc/t-Bu (A) and Boc/Bn (B) protecting-group strategies applied in SPPS. (A) The Fmoc-group is removed by β-elimation through piperidine and t-Bu is released by acidolysis with TFA. (B) Cleavage of protecting groups with TFA and HF occurs by acidolysis. Removal reactions of the

The influence of intraannular templates on the liquid crystallinity of shape-persistent macrocycles

• Joscha Vollmeyer,
• Ute Baumeister and
• Sigurd Höger

Beilstein J. Org. Chem. 2014, 10, 910–920, doi:10.3762/bjoc.10.89

• catalysts and 1,4-benzoquinone as oxidant, the precursor is finally intramolecular cyclized in THF/piperidine under high-dilution conditions by slowly adding (48 hours) a solution of the tetraacetylene to the reaction media. Gel permeation chromatography (GPC) analysis of the crude product indicates that

• can be omitted. For this purpose, we performed the cyclization towards macrocycle 1c not under pseudo high-dilution conditions but by stirring a solution of the complete starting material of 1c at once in THF, piperidine, Pd(PPh3)Cl2 and CuI as catalysts and 1,4-benzoquinone as oxidant for 3 h at 60

• omitted for clarity); (c) visualization of the intraannular alkyl chain packing within the columns. Synthesis of macrocycle 1a with an intraannular undecanedioxy bridge. a: Pd(PPh3)2Cl2, PPh3, CuI, piperidine, 84%; b: TBAF, THF, 94%; c: Pd(PPh3)2Cl2, CuI, 1,4-benzoquinone, piperidine, THF, 49%. Synthesis

Addition of H-phosphonates to quinine-derived carbonyl compounds. An unexpected C9 phosphonate–phosphate rearrangement and tandem intramolecular piperidine elimination

• Łukasz Górecki,
• Artur Mucha and
• Paweł Kafarski

Beilstein J. Org. Chem. 2014, 10, 883–889, doi:10.3762/bjoc.10.85

• skeleton and a phosphorus atom. For the C9 ketones a phosphonate–phosphate rearrangement, associated with a tandem elimination of the piperidine fragment, was evidenced. Keywords: carbonyl derivatives; dialkyl phosphite addition; organophosporus; phosphonate–phosphate rearrangement; quinine oxidation

• were not visible (Scheme 5), what demonstrated a degradation of the bicyclic fragment of quinuclidine to a piperidine skeleton. In addition, the characteristic signal of the H11 proton was absent and the H12 resonance was shifted to the lower field (5.43 ppm), between the H20 and H21 vinyl protons. The

• novel contribution to the reactivity of quinine although similar eliminations of piperidine in Cinchona alkaloids have been reported in the literature. Accordingly, heating of quinine or derivatives in acids provided either quino-/cinchotoxine ketones or their tautomeric enol esters, depending on the

Integration of enabling methods for the automated flow preparation of piperazine-2-carboxamide

• Richard J. Ingham,
• Claudio Battilocchio,
• Joel M. Hawkins and
• Steven V. Ley

Beilstein J. Org. Chem. 2014, 10, 641–652, doi:10.3762/bjoc.10.56

• (shown highlighted with a box) and report its height from the bottom of the image. Flow set up for the automated machine assisted synthesis of (R,S)-piperidine-2-carboxamide. Control sequence for the two-step process. Chart of monitored parameters over a 15 hour reaction. The output from the hydrolysis

Silver and gold-catalyzed multicomponent reactions

• Giorgio Abbiati and
• Elisabetta Rossi

Beilstein J. Org. Chem. 2014, 10, 481–513, doi:10.3762/bjoc.10.46

• , phenylacetylene and piperidine in dioxane at 100 °C in open air [14]. Although the scope was not investigated, the authors observed that the activity of the catalyst was notably affected by the nature of the anion in the order Cl > Br >> I. They argued that the true catalytic species would be a structurally

• catalysts for coupling arylaldehydes, piperidine and phenylacetylene in toluene at 100 °C. One year later, the same research group obtained comparable results under identical reaction conditions by using gold(0) nanoparticles stabilized by nanocristalline magnesium oxide [28]. In this work, the scope was

Practical synthesis of aryl-2-methyl-3-butyn-2-ols from aryl bromides via conventional and decarboxylative copper-free Sonogashira coupling reactions

• Andrea Caporale,
• Stefano Tartaggia,
• Andrea Castellin and
• Ottorino De Lucchi

Beilstein J. Org. Chem. 2014, 10, 384–393, doi:10.3762/bjoc.10.36

• in piperidine as the solvent [39][78] or by using aminophosphines [18] as well as phenanthryl imidazolium carbenes as the catalyst ligands [79]. A more practical methodology has been reported by Shirakawa in which a Pd(OAc)2/PPh3 catalyst system in DMSO and in the presence of K3PO4 as the base was

• , typically employed in conventional Pd/Cu Sonogashira coupling protocols, resulted in poor yields of our desired product (Table 1, entries 4–6). Piperidine, which has been reported to efficiently perform copper-free coupling reactions of 4 with polycyclic aryl bromides [77], gave only 17% yield with our

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

• was only separable by chromatography requiring significantly increased amounts of silica gel (the crude product weight usually obtained 300–400% of the theoretical yield after aqueous work up). Attempts to crystallize OPPh3 beside the piperidine 11a or of the fumaric acid salt of 11a for instance

• declined. Moreover, the reaction temperature has a strong influence: When the condensation of 9a had been performed at −20 °C for instance, piperidine 11a was isolated in only 41% yield (Table 2, entry 9). Interestingly, the activation of the primary OH function of substrates 9 in the presence of the

• : Pyrrolidine 13a was formed in 80% yield after hydrolysis of the phosphate and in 81% yield after extraction of triethylphosphate with EtOAc (×5) while keeping the product 13a as the hydrochloride salt in the aqueous phase (Table 3, entries 1 and 2). Surprisingly, with the higher homologue 12b the piperidine

Four-component reaction of cyclic amines, 2-aminobenzothiazole, aromatic aldehydes and acetylenedicarboxylate

• Hong Gao,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2013, 9, 2934–2939, doi:10.3762/bjoc.9.330

• Hong Gao Jing Sun Chao-Guo Yan College of Chemistry & Chemical Engineering, Yangzhou University, Yangzhou 225002, China 10.3762/bjoc.9.330 Abstract The four-component reaction of 2-aminobenzothiazole, aromatic aldehydes, acetylenedicarboxylate and piperidine or pyrrolidine in ethanol afforded the

• spiro compounds by using the in situ generated Huisgen 1,4-dipoles [17][18][19][20][21][22][23][24]. During these research works, we noticed that even through the cyclic secondary amines such as pyrrolidine, piperidine and morpholine also reacted with electron-deficient alkynes to give the Huisgen 1,4

• benzothiazolyl and piperidinyl (or pyrrolidinyl) units. Results and Discussion Initially, we set out to investigate the reaction conditions by using piperidine to react with dimethyl acetylenedicarboxylate to give the expected β-enamino ester. It is interesting to find that the reaction of piperidine with

Stereoselectively fluorinated N-heterocycles: a brief survey

• Xiang-Guo Hu and
• Luke Hunter

Beilstein J. Org. Chem. 2013, 9, 2696–2708, doi:10.3762/bjoc.9.306

• bioavailability of 38 was poor, and this was attributed to the basicity of the secondary amine group which made the molecule positively charged at physiological pH and hence unable to traverse biological membranes. This problem was overcome by introducing a fluorine atom onto the piperidine ring (39): the

Synthesis of homo- and heteromultivalent carbohydrate-functionalized oligo(amidoamines) using novel glyco-building blocks

• Felix Wojcik,
• Sinaida Lel,
• Alexander G. O’Brien,
• Peter H. Seeberger and
• Laura Hartmann

Beilstein J. Org. Chem. 2013, 9, 2395–2403, doi:10.3762/bjoc.9.276

• stable towards piperidine exposure and the activated species should selectively react with primary amines without prior decomposition. Indeed, all glyco-building blocks described here, fulfil these criteria and can be applied for sequential coupling under PyBop or HATU activation and Fmoc deprotection

• with 25% piperidine in DMF on solid support (Figure 3). Final deprotection from the resin was performed with TFA/DCM mixtures, followed by acetyl deprotection in solution under Zemplén conditions [44]. Although the glycosylated building blocks 9–13 suffer from steric hindrance and have a relatively

Towards stereochemical control: A short formal enantioselective total synthesis of pumiliotoxins 251D and 237A

• Jie Zhang,
• Hong-Kui Zhang and
• Pei-Qiang Huang

Beilstein J. Org. Chem. 2013, 9, 2358–2366, doi:10.3762/bjoc.9.271

• -benzyloxycarbonyl group imposed A1,3-strain on piperidine derivatives founded the basis for the observed stereocontrol. Thus, we chose keto-lactam 10 as our substrate. Although compound 10 is not a urethane, and a A1,3-strain not longer exists, a simple chair conformational-controlled preferential equatorial attack

• ) (60–90 °C) mixture. (R)-3-(tert-Butyldimethylsilyloxy)-1-(4-methoxybenzyl)piperidine-2,6-dione (14): To a solution of (R)-3-hydroxy-1-(4-methoxybenzyl)piperidine-2,6-dione 19 [47] (125 mg, 0.5 mmol), DMAP (10 mg) and imidazole (67 mg, 1 mmol) in CH2Cl2 (15 mL) was added TBDMSCl (52 μL, 0.6 mmol). The

• . (S)-6-(But-3-en-1-yl)-1-(4-methoxybenzyl)piperidine-2,5-dione (10): To a stirred solution of compound 18 (100 mg, 0.34 mmol) in CH2Cl2 (5 mL) was added Dess–Martin periodinane (220 mg, 0.52 mmol) at room temperature. After being stirred for 2 h, the reaction was quenched with a 10% aqueous solution