Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

• elements, like a pyrrolidine, a furan-2-one, an oxazolidinone and particularly a 3,4-furylidene moiety in the polyketide part. An analysis of the gene cluster as well as feeding experiments with isotope-labelled precursors led to a proposal for the formation of the furan ring [69][70]. The anticipated

Development of chiral metal amides as highly reactive catalysts for asymmetric [3 + 2] cycloadditions

• Yasuhiro Yamashita,
• Susumu Yoshimoto,
• Mark J. Dutton and
• Shū Kobayashi

Beilstein J. Org. Chem. 2016, 12, 1447–1452, doi:10.3762/bjoc.12.140

• Schiff bases of glycine ester that proceed with low catalyst loadings (ca. 0.01 mol %). Catalytic asymmetric [3 + 2] cycloadditions of Schiff bases of α-amino esters to olefins are useful for synthesizing optically active pyrrolidine derivatives [10][11][12], and many highly stereoselective reactions

• through the efficient formation of pseudo-intramolecular transition state A. Intermediate B reacted with maleimide 2a to form Cu-pyrrolidine intermediate C. H-HMDS then reacted with the latter to regenerate the chiral CuHMDS and release the product to complete the catalytic cycle. The result obtained by

• using a mesitylcopper catalyst suggests that the reaction could also proceed through a product base mechanism in which the Cu-pyrrolidine intermediate C deprotonates the Schiff base 1a directly; however, the higher reactivity observed upon catalysis by CuHMDS and the basicity of the intermediate

Chiral cyclopentadienylruthenium sulfoxide catalysts for asymmetric redox bicycloisomerization

• Barry M. Trost,
• Michael C. Ryan and
• Meera Rao

Beilstein J. Org. Chem. 2016, 12, 1136–1152, doi:10.3762/bjoc.12.110

• opening of either 49 or its vinylcyclopropane precursor 48 was observed. Finally, styrenyl substrates like 50 can be used for redox bicycloisomerization, but their pyrrolidine products are isolated in somewhat diminished enantioselectivities. After examining the scope of the redox bicycloisomerization

Antibacterial structure–activity relationship studies of several tricyclic sulfur-containing flavonoids

• Lucian G. Bahrin,
• Henning Hopf,
• Peter G. Jones,
• Laura G. Sarbu,
• Cornelia Babii,
• Alina C. Mihai,
• Marius Stefan and
• Lucian M. Birsa

Beilstein J. Org. Chem. 2016, 12, 1065–1071, doi:10.3762/bjoc.12.100

• amino group bound to the 1,3-dithiolium cycle (ring D). Upon testing these flavonoids against Staphylococcus aureus and comparing the results with those obtained for 1, we concluded that the antibacterial activity for tricyclic flavonoids of type 5 decreases in the order NEt2 > pyrrolidine > NMe2

Opportunities and challenges for direct C–H functionalization of piperazines

• Zhishi Ye,
• Kristen E. Gettys and
• Mingji Dai

Beilstein J. Org. Chem. 2016, 12, 702–715, doi:10.3762/bjoc.12.70

• -studied pyrrolidine and piperidine systems, the existence of the second ring-bound nitrogen in piperazines either causes various side reactions or inhibits or diminishes the reactivity of the C–H bond. This review summarizes the current status and challenges of direct C–H bond functionalization of

• atoms [30][31]. Corresponding enantioselective versions have also been developed using chiral diamines as ligands to allow access to enantioenriched α-substituted nitrogen heterocycles. However, most of the success has been made in the territory of N-Boc-pyrrolidine [32][33] and N-Boc-piperidine [34][35

• the corresponding substituents on the α-carbon of N-Boc-N’-benzylpiperazines in good yield. Notably, the O’Brien–Campos conditions work well for N-Boc-pyrrolidine and imidazolidine, but not for N-Boc-piperidine (cf. 20). Asymmetric direct α-C–H lithiation trapping Advances of enantioselective α

cis–trans-Amide isomerism of the 3,4-dehydroproline residue, the ‘unpuckered’ proline

• Vladimir Kubyshkin and
• Nediljko Budisa

Beilstein J. Org. Chem. 2016, 12, 589–593, doi:10.3762/bjoc.12.57

• Pro structural analogues, azetidine-2-carboxylic acid (norproline) and pipecolic acid (homoproline) [4], it appears that the high isomerization barrier is a feature associated with the 5-membered pyrrolidine ring of Pro [5]. The pyrrolidine ring of Pro can be found in several conformations, designated

• pyrrolidine ring, approaching to C3 and C4 atoms [47]. Repulsion between the oxygen lone pairs and the double bond in the Dhp residue could cause the experimentally evident increase in the rotation barriers. Conclusion In summary, we performed the experimental characterization of proline analogues with a 3,4

(Thio)urea-mediated synthesis of functionalized six-membered rings with multiple chiral centers

• Giorgos Koutoulogenis,
• Nikolaos Kaplaneris and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2016, 12, 462–495, doi:10.3762/bjoc.12.48

• is highly noted that the difference to the moiety at the 4-position of the pyrrolidine ring, where a fluorine atom exists, gives to the organocatalyst 50 the ability to catalyze this tandem Michael–Henry reaction in brine, giving excellent diastereoselectivity and enantiomeric excess, unlike the

• previously employed catalyst 47, which worked only in organic solvent. The key component for the achievement of catalyst’s 50 catalytic ability is the known "gauche effect" of fluorine in the pyrrolidine ring, where σ*(C–F) and σ(C–H) vicinal orbitals tend to overlap [28]. For a more efficient overlap of

• order to complete the cascade, the authors employed a bifunctional thiourea 156 and pyrrolidine in an one-pot protocol. Overall, the reaction proceeded smoothly and the products were obtained in moderate to good yields (up to 70%), but in excellent selectivities (>95:5 dr and up to 99% ee). Recently

Tandem processes promoted by a hydrogen shift in 6-arylfulvenes bearing acetalic units at ortho position: a combined experimental and computational study

• Mateo Alajarin,
• Marta Marin-Luna,
• Pilar Sanchez-Andrada and
• Angel Vidal

Beilstein J. Org. Chem. 2016, 12, 260–270, doi:10.3762/bjoc.12.28

• [f]indenes 5 and 6. Reagents and conditions: i) cyclopentadiene, pyrrolidine, anhydrous methanol, rt, 10 h; ii) DMSO, microwave, 120 °C, 120 W, 20–40 min. Postulated reaction path for the conversion 3a → 5a + 6a initiated by a [1,4]-hydride shift. Alternative mechanistic paths for the conversion 3a

• ) triethylamine (10%), DMSO, rt, 2 h. Preparation of benz[f]indenes 25 and 26. Reagents and conditions: i) cyclopentadiene, pyrrolidine, anhydrous methanol, rt, 10 h; ii) DMSO, microwave, 120 °C, 120 W, 20–40 min. Mechanistic paths for the conversion of fulvene 3a into the benz[f]indenes 5a and 6a showing the

Asymmetric α-amination of β-keto esters using a guanidine–bisurea bifunctional organocatalyst

• Minami Odagi,
• Yoshiharu Yamamoto and
• Kazuo Nagasawa

Beilstein J. Org. Chem. 2016, 12, 198–203, doi:10.3762/bjoc.12.22

• the guanidine moiety (Table 1, entries 5 and 6). A catalyst bearing a six-membered ring at R1 and R2 (1e) gave excellent yield, but with only 27% ee (Table 1, entry 5). Interestingly, catalyst 1f bearing a pyrrolidine ring at R1 and R2 showed the highest selectivity, and 5a was obtained in 99% yield

Exploring architectures displaying multimeric presentations of a trihydroxypiperidine iminosugar

• Camilla Matassini,
• Stefania Mirabella,
• Andrea Goti,
• Inmaculada Robina,
• Antonio J. Moreno-Vargas and
• Francesca Cardona

Beilstein J. Org. Chem. 2015, 11, 2631–2640, doi:10.3762/bjoc.11.282

• bioactive molecules (namely pyrrolidine- and pyrrolizidine-based iminosugars) [19][20][21]. Moreover, trivalent pyrrolidine derivatives have been recently employed to probe the multivalent effect towards α-L-fucosidase inhibition [22], which may be clinically relevant in the treatment of fucosidosis

Beyond catalyst deactivation: cross-metathesis involving olefins containing N-heteroaromatics

• Kevin Lafaye,
• Cyril Bosset,
• Lionel Nicolas,
• Amandine Guérinot and
• Janine Cossy

Beilstein J. Org. Chem. 2015, 11, 2223–2241, doi:10.3762/bjoc.11.241

• by focusing on amine-mediated degradation of GII and they highlighted various plausible decomposition pathways depending on the nature of the amine [45]. At first, the reaction between GII and various amines such as n-butylamine (a), pyrrolidine (b), morpholine (c) and DBU (d) were examined by 1H NMR

• NMR experiments [45]. The steric hindrance of the amine appeared to be a critical parameter. The non-bulky primary amine n-butylamine (a) induced a fast decomposition of the methylidene 2 (Table 1, entry 1) whereas secondary amines such as pyrrolidine (b) and morpholine (c) are less detrimental to the

• increased Brønsted basicity of the amine seemed to induce a faster deactivation of the catalyst. In addition, when the self-metathesis of styrene was performed in the presence of pyrrolidine, DBU or Et3N, olefin 22 was formed as the major product (Scheme 9). To explain these observations, a deactivation

Photoinduced 1,2,3,4-tetrahydropyridine ring conversions

• Baiba Turovska,
• Henning Lund,
• Viesturs Lūsis,
• Anna Lielpētere,
• Edvards Liepiņš,
• Sergejs Beljakovs,
• Inguna Goba and
• Jānis Stradiņš

Beilstein J. Org. Chem. 2015, 11, 2166–2170, doi:10.3762/bjoc.11.234

• ; photoinduced electron transfer; pyrrolidine; tetrahydropyridine; Introduction Increased attention has been paid to the chemistry of cyclic organic peroxides since it was found that naturally occurring representatives of this group possess biological activity, particular antimalarial [1][2]. Significantly less

Recent applications of ring-rearrangement metathesis in organic synthesis

• Sambasivarao Kotha,
• Milind Meshram,
• Priti Khedkar,
• Shaibal Banerjee and
• Deepak Deodhar

Beilstein J. Org. Chem. 2015, 11, 1833–1864, doi:10.3762/bjoc.11.199

• generated the spiroannulated pyrrolidine 249 in 68% yield. However, when the reaction was performed in toluene at 80 °C, the isomeric tricyclic compound 250 was afforded in 34% yield and tricyclic derivative 249 was obtained in 37% yield (Scheme 51). Rainier’s group [52] has successfully demonstrated the

Preparative semiconductor photoredox catalysis: An emerging theme in organic synthesis

• David W. Manley and
• John C. Walton

Beilstein J. Org. Chem. 2015, 11, 1570–1582, doi:10.3762/bjoc.11.173

• in an aqueous dispersion of a Pt-TiO2 catalyst, an interesting self-reaction occurred. Ohtani and co-workers isolated modest yields of secondary amines 13 that were formed via C–N coupling (Scheme 4, top) [48]. Terminal diamines reacted by ring closure resulting in cyclic amines 14; pyrrolidine was

Development of variously functionalized nitrile oxides

• Haruyasu Asahara,
• Keita Arikiyo and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2015, 11, 1241–1245, doi:10.3762/bjoc.11.138

• °C was required for the substitution reaction by sec-butylamine. However, in the case of tert-butylamine, even when the reaction was conducted in a sealed tube at 120 °C, only a small amount of amide was observed (Table 2, entries 7–10). On the other hand, a cyclic secondary amine, pyrrolidine

Synthesis of multivalent carbohydrate mimetics with aminopolyol end groups and their evaluation as L-selectin inhibitors

• Joana Salta,
• Jens Dernedde and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2015, 11, 638–646, doi:10.3762/bjoc.11.72

• attempts changing reaction time and equivalents of protected aminopyran 3 and succinic acid dichloride, neither the desired product 6 nor the corresponding pyrrolidine-2,5-dione resulting from an intramolecular reaction were formed. It was quite unexpected that we could not achieve this transformation

Novel stereocontrolled syntheses of tashiromine and epitashiromine

• Loránd Kiss,
• Enikő Forró and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2015, 11, 596–603, doi:10.3762/bjoc.11.66

• –cyclization [27], or electrophilic pyrolidinone alkylation followed by ring closure [28][29]. Pyrrolidine alkylation and nucleophilic ring closure followed by C–C double bond hydroboration [30] leads to racemic epitashiromine, as does the N-alkylated succinimide transformation through the corresponding

• intramolecular cyclization of a chiral alkenylated pyrrolidinone, followed by hydroxylation [32], or by the intramolecular ring closure of chiral pyrrolidine diesters followed by ester and oxo group reduction [33], while the syntheses of (+)-epitashiromine starts from a chiral morpholine derivative, with nitrone

• pyrrole, followed by saturation [37]. The transformation of chiral functionalized pyrrole or pyrrolidine derivatives has served as the basis of the construction of (−)-epitashiromine [38][39] (Figure 4). The oxidative functionalization of cyclic β-amino acid derivatives has been reported to be a

Attempts to prepare an all-carbon indigoid system

• Şeref Yildizhan,
• Henning Hopf and
• Peter G. Jones

Beilstein J. Org. Chem. 2015, 11, 363–372, doi:10.3762/bjoc.11.42

• mirror symmetry (rmsd 0.04 Å). Our final attempt for the present to prepare a precursor hydrocarbon for an all-carbon indigoid system rests on the observation that the Thiele condensation of indene (6) with acetone in pyrrolidine/methanol yields the benzofulvene 29 (Scheme 6). A suitable methylene

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

• into the synthesis of functionalised peptides and peptidomimetics using the anode oxidation strategy [91][92][93][94][95]. The anodic oxidation of pyrrolidine derivatives and silylated peptides afforded a variety of bicyclic lactam peptidomimetics and functionalised peptides (Scheme 22) [91][92][94

Recent advances in the electrochemical construction of heterocycles

• Robert Francke

Beilstein J. Org. Chem. 2014, 10, 2858–2873, doi:10.3762/bjoc.10.303

• , resulting in N-tosylated pyrrolidine products (Scheme 2, X = NHTs) [35][36]. The reactions can be carried out under galvanostatic conditions (C.C.E. = constant current electrolysis) at room temperature in an undivided cell using a vitreous carbon anode. The presence of a proton scavenger is necessary in

A new charge-tagged proline-based organocatalyst for mechanistic studies using electrospray mass spectrometry

• J. Alexander Willms,
• Rita Beel,
• Martin L. Schmidt,
• Christian Mundt and
• Marianne Engeser

Beilstein J. Org. Chem. 2014, 10, 2027–2037, doi:10.3762/bjoc.10.211

• -((3S,5S)-1,5-Bis(tert-butoxycarbonyl)pyrrolidine-3-yloxy)phenyl)-1-ethylpyridinium bromide (9): (2S,4S)-tert-Butyl N-tert-butoxycarbonyl-4-(4-(pyridine-4-yl)phenoxy)prolinate (8, 0.22 g, 0.5 mmol) was dissolved in bromoethane (13.0 mL, 174.2 mmol), heated to 43 °C and stirred for 5 d. Bromoethane was

Pyrrolidine nucleotide analogs with a tunable conformation

• Lenka Poštová Slavětínská,
• Dominik Rejman and
• Radek Pohl

Beilstein J. Org. Chem. 2014, 10, 1967–1980, doi:10.3762/bjoc.10.205

• Lenka Postova Slavetinska Dominik Rejman Radek Pohl Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic 10.3762/bjoc.10.205 Abstract Conformational preferences of the pyrrolidine ring in nucleotide analogs

• 7–14 were investigated by means of NMR and molecular modeling. The effect of the relative configuration of hydroxy and nucleobase substituents as well as the effect of the alkylation or acylation of the pyrrolidine nitrogen atom on the conformation of the pyrrolidine ring were studied. The results

• of a conformational analysis show that the alkylation/acylation can be effectively used for tuning the pyrrolidine conformation over the whole pseudorotation cycle. Keywords: conformation; NMR; nucleic acids; nucleotide analog; phosphonic acid; pseudorotation; pyrrolidine; Introduction Nucleotides

Facile synthesis of 1-alkoxy-1H-benzo- and 7-azabenzotriazoles from peptide coupling agents, mechanistic studies, and synthetic applications

• Mahesh K. Lakshman,
• Manish K. Singh,
• Mukesh Kumar,
• Raghu Ram Chamala,
• Vijayender R. Yedulla,
• Domenick Wagner,
• Evan Leung,
• Lijia Yang,
• Asha Matin and
• Sadia Ahmad

Beilstein J. Org. Chem. 2014, 10, 1919–1932, doi:10.3762/bjoc.10.200

• ][1,2,3]triazole, via in situ formation of pyrrolidine enamines and Pd catalysis. Keywords: alkoxy; azabenzotriazole; benzotriazole; peptide-coupling; phosphonium; Introduction Benzotriazole derivatives are of importance in diverse contexts. As examples, in medicinal chemistry substituted benzotriazoles

• ]. Exposure of 1.5 molar equiv each of cyclohexanone, N-benzylpiperidone, and 4-tert-butylcyclohexanone to compound 1g, Pd(PPh3)4 (5 mol %), and pyrrolidine (30 mol %) in DMSO at room temperature, led to the corresponding γ,δ-unsaturated cycloalkanones (Figure 4). Good yields of products 18 and 19 were

• , the enamine was formed in situ in this study, with catalytic pyrrolidine. These results appear to indicate that the easily synthesized allylic benzotriazolyl derivatives described herein may be promising reagents for the α-allylation of carbonyl compounds. As a final note, while this work was in

Synthesis of rigid p-terphenyl-linked carbohydrate mimetics

• Maja Kandziora and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 1749–1758, doi:10.3762/bjoc.10.182

• close proximity to the C-5 hydroxy group and leads to a nucleophilic substitution under formation of the pyrrolidine moiety. This process is possibly promoted by samarium(III) which can act as Lewis acid and by the steric demanding TBS group which decreases the distance between the two functional groups

• hydrogenolysis, zinc/acid or samarium diiodide were tested. For each of the substrates the suitable method has to be found. By the N–O bond cleavage of compound 12a with samarium diiodide an unexpected bicyclic pyrrolidine derivative 24 was isolated. The prepared unnatural C-aryl glycosides could find

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

• non-nucleoside substrates (Schemes 7–9). Filichev et al. used pyrrolidine 16, paraformaldehyde and uracil for the preparation of the Mannich base 17, which is considered as an 1'-aza-analog of pseudouridine (Scheme 7) [66]. Information on application of compound 17 was not given. By employing

• pyrrolidine hydrochlorides 16*HCl or 20a–c*HCl (Scheme 8), Evans et al. developed a concise synthesis of 1'-aza-analogs of immucilins, compounds 19 and 21 [67]. The amine hydrochlorides were treated in aq acetate buffer with aq formaldehyde and 9-deazaguanine 18a or a variety of deazapurines 18b–e. The