Multicomponent synthesis of spiropyrrolidine analogues derived from vinylindole/indazole by a 1,3-dipolar cycloaddition reaction

• Manjunatha Narayanarao,
• Lokesh Koodlur,
• Vijayakumar G. Revanasiddappa,
• Subramanya Gopal and
• Susmita Kamila

Beilstein J. Org. Chem. 2016, 12, 2893–2897, doi:10.3762/bjoc.12.288

• stereospecific cyclic adducts. Keywords: L-proline; ninhydrin; sarcosine; spiropyrrolidine; 5-vinylindazole; 5-vinylindole; Introduction The [3 + 2] cycloaddition between azomethine ylides and olefins/acetylene as dipolarophiles is an important reaction to access a number of novel heterocyclic spiro scaffolds

• in the construction of functionalized spiro compounds. We report herein the facile synthesis of novel spiropyrrolidine compounds through a one-pot three-component reaction involving N-substituted vinylindole/indazole, ninhydrin and sarcosine/L-proline. The present multicomponent reaction (MCR) leads

• cyclic amino acid L-proline (6) which was reacted with 3 under the optimized reaction conditions. The corresponding stereo- and regiospecific isomers of spiropyrrolidines 8 were obtained in good yields (Table 1, entries 12–22). The stereochemical assignments for compounds 8 were supported by 2D NMR data

Interactions between cyclodextrins and cellular components: Towards greener medical applications?

• Loïc Leclercq

Beilstein J. Org. Chem. 2016, 12, 2644–2662, doi:10.3762/bjoc.12.261

• ., alanine, valine, leucine, isoleucine, proline, phenylalanine, tryptophan, cysteine and methionine), they can be easily included inside the CDs. This complexation leads to modification of the protein. For sake of clarity, only some typical examples are reported in this section. In their paper on the

Towards the development of continuous, organocatalytic, and stereoselective reactions in deep eutectic solvents

• Davide Brenna,
• Elisabetta Massolo,
• Alessandra Puglisi,
• Sergio Rossi,
• Giuseppe Celentano,
• Maurizio Benaglia and
• Vito Capriati

Beilstein J. Org. Chem. 2016, 12, 2620–2626, doi:10.3762/bjoc.12.258

• synthesis of enantiomerically enriched products by testing different experimental set-ups. L-Proline-catalysed cross-aldol reactions were efficiently performed in continuo, with high yield (99%), anti-stereoselectivity, and enantioselectivity (up to 97% ee). Moreover, using two different DES mixtures, the

• . Keywords: continuous process; DES; organocatalysis; proline; stereoselective aldol reaction; Introduction The aldol reaction is a powerful synthetic tool to create new C–C bonds [1]. It offers several possibilities to control the stereochemical outcome of the process and to afford stereochemically defined

• chiral products [2]. Among all the possible options, the L-proline-catalysed stereoselective cross-aldol reaction remains the greener choice. After the pioneering works by List and Barbas [3], a huge effort was made by the scientific community to improve both the yield and the stereoselectivity of the

Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis

• Darcy J. Atkinson,
• Briar J. Naysmith,
• Daniel P. Furkert and
• Margaret A. Brimble

Beilstein J. Org. Chem. 2016, 12, 2325–2342, doi:10.3762/bjoc.12.226

• -enduracididine by Yuan et al.: In 2015, Yuan et al. reported their synthesis of protected L-allo-enduracididine 63 from L-4-hydroxyproline 64 (Scheme 12) [66]. The C-4 stereocentre was installed through inversion of the hydroxy group of proline derivative 64 via mesylation and azide displacement to afford 65

p-Nitrophenyl carbonate promoted ring-opening reactions of DBU and DBN affording lactam carbamates

• Madhuri Vangala and
• Ganesh P Shinde

Beilstein J. Org. Chem. 2016, 12, 2086–2092, doi:10.3762/bjoc.12.197

• explore the structural diversity using different p-nitrophenyl carbonates which were prepared by treating an alcohol with p-nitrophenyl chloroformate in CH2Cl2 using pyridine as a base. Thus, homopropargyl alcohol, decanol, cholesterol and N-Boc-trans-4-hydroxy-L-proline methyl ester gave the

• -caprolactam of N-Boc-trans-4-hydroxy-L-proline methyl ester 5b, rotamers due to flipping of the N-Boc group were obtained. Owing to the importance of sugar caprolactams in polymerizations, 2,3-di-O-benzyl-4-O-p-methoxybenzyl-α-methyl-D-glucopyranoside and 2,3,4-tri-O-benzoyl-α-methyl-D-glucopyranoside [30][31

Stereo- and regioselectivity of the hetero-Diels–Alder reaction of nitroso derivatives with conjugated dienes

• Lucie Brulíková,
• Aidan Harrison,
• Marvin J. Miller and
• Jan Hlaváč

Beilstein J. Org. Chem. 2016, 12, 1949–1980, doi:10.3762/bjoc.12.184

• )-alkoxyamine 123. The reaction of the L-proline derivative 124 and its analogues 125 and 126 with cyclohexadiene (120) gave relatively low de values [112] (Scheme 25). A more comprehensive study on amino acid based acylnitroso dienophiles was performed by Miller et al. [28][113]. For a number of L- and D-amino

• acids and derivatives 129, including proline-derived dienophiles, the stereoselectivity of the reaction with cyclopentadiene (130) was tested, and again only a modest size-dependent (R1) stereoselectivity was found for the products 131 (Table 3). Some more extensive studies on reactions of proline or

Mechanistic investigations on six bacterial terpene cyclases

• Patrick Rabe,
• Thomas Schmitz and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2016, 12, 1839–1850, doi:10.3762/bjoc.12.173

• moiety of the substrate [26]. Mutation within these conserved motifs is usually critical for enyzme functionality [26][41]. The (−)-α-amorphene synthase from S. viridochromogenes DSM 40736 displays the aspartate-rich motif (105DDRAE), the NSE triad (242PDLFSAVKE) starting with a proline instead of the

• usual asparagine, obviously without effect on the enzyme function, the pyrophosphate sensor R-196 and the 327RY dimer. Terpene cyclases with close homology are encoded in more than 40 genome sequenced streptomycetes that all show an altered NSE triad starting with either proline or alanine. The closest

Rh-Catalyzed reductive Mannich-type reaction and its application towards the synthesis of (±)-ezetimibe

• Motoyuki Isoda,
• Kazuyuki Sato,
• Yurika Kunugi,
• Satsuki Tokonishi,
• Atsushi Tarui,
• Masaaki Omote,
• Hideki Minami and
• Akira Ando

Beilstein J. Org. Chem. 2016, 12, 1608–1615, doi:10.3762/bjoc.12.157

• asymmetric Mannich reaction using a Lewis acid catalyst [1]. (L)-Proline is known as an excellent promoter for the Mannich reaction [2][3][4][5][6], and besides this, the reaction of the silyl enol ether derivatives with imines was used as an effective method [7][8][9]. In this situation, a wide variety of

Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

• Mohammad Haji

Beilstein J. Org. Chem. 2016, 12, 1269–1301, doi:10.3762/bjoc.12.121

• ]. The desired phosphono-substituted pyrroles were isolated in 41–87% yield under solvent and catalyst-free conditions. Kaboudin et al. described a three-component, catalyst-free decarboxylative coupling of proline (296) with aldehydes 297 and dialkyl phosphonates to afford pyrrolidinylphosphonates 300

• . The corresponding pyrrolidinylphosphonates 300 were isolated in 43–86% yields under refluxing in toluene (Scheme 61) [99]. The reaction was proposed to proceed through the condensation of proline with an aldehyde under formation of oxazolidin-5-ones 298 followed by decarboxylation to give the

• proline with aldehydes and dialkyl phosphites for the synthesis of pyrrolidinylphosphonates. Three-component domino aza-Wittig/phospha-Mannich sequence for the phosphorylation of isatin derivatives. Stereoselective synthesis of phosphorylated trans-1,5-benzodiazepines via a one-pot three-component

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• proline and its derivatives [31]. Recently, Hoveyda and co-workers designed a novel amino acid amide catalyst (cat. 4) for the asymmetric addition of unsaturated organoboranes to carbonyls and imines, producing the corresponding enantiomerically pure alcohols and amines in excellent yields [32]. As shown

• cyanomethylation of isatins with cyanoacetic acid using the L-proline-derived thiourea as the catalyst (cat. 30), giving the cyanomethylated products in good yields (up to 82%) and with excellent enantioselectivities (up to 90% ee, Scheme 44) [61]. The reactions were performed in methyl tert-butyl ether at room

1H-Imidazol-4(5H)-ones and thiazol-4(5H)-ones as emerging pronucleophiles in asymmetric catalysis

• Antonia Mielgo and
• Claudio Palomo

Beilstein J. Org. Chem. 2016, 12, 918–936, doi:10.3762/bjoc.12.90

• (Scheme 2, compounds 13–15) proceeded with poor diastereocontrol but the results were improved by changing to catalyst C2 [62]. Nonetheless, in both cases the enantioselectivity for the major diastereomer was excellent. Finally, and starting from the corresponding bicyclic imidazolones, quaternary proline

Gold-catalyzed direct alkynylation of tryptophan in peptides using TIPS-EBX

• Gergely L. Tolnai,
• Jonathan P. Brand and
• Jerome Waser

Beilstein J. Org. Chem. 2016, 12, 745–749, doi:10.3762/bjoc.12.74

• other aromatic amino acids, such as phenylalanine or tyrosine (products 5c and 5d). Serine and proline containing dipeptides 5e and 5f could also be obtained in 64% and 53% yield, respectively. The reaction was therefore general for dipeptides bearing tryptophan at the C-terminus. On the other hand

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

• Vladimir Kubyshkin Nediljko Budisa Institute of Chemistry, Technical University of Berlin, Müller-Breslau-Str., 10, 10623, Berlin, Germany 10.3762/bjoc.12.57 Abstract Proline (Pro) is an outstanding amino acid in various biochemical and physicochemical perspectives, especially when considering

• isomerism; fluorine; pKa; proline; Introduction The sole genetically encoded secondary amino acid proline (Pro, 1) is known for its unique properties in biological systems. In particular, Pro residues are often found in the s-cis peptidyl-Pro conformation, due to the low energy difference between the s

• reasons. However, it has also been reported that N-acylated pyroglutamic acid exhibits almost exclusively the s-trans amide conformation despite being formally a 5-substituted Pro [22]. The conformational preferences of the heterocyclic analogues of proline [23][24][25] and, in particular, pseudoprolines

The aminoindanol core as a key scaffold in bifunctional organocatalysts

• Isaac G. Sonsona,
• Eugenia Marqués-López and
• Raquel P. Herrera

Beilstein J. Org. Chem. 2016, 12, 505–523, doi:10.3762/bjoc.12.50

• incorporated into proline derivatives has been scarcely explored. Herein, the most representative and illustrative examples are compiled and this review will be mainly focused on the cases where the aminoindanol moiety confers bifunctionality to the organocatalysts. Keywords: aminocatalysis; 1,2-aminoindanol

(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

• of intermediates have been proposed to be the reactive intermediates in many reactions such as aldol, Michael, Mannich, and α-functionalization (α-chlorination, α-amination, α-fluorination) reactions. Proline-type organocatalysts are considered priviliged, because their corresponding enamines exist

• enolate of cyclohexanone. Two subsequent aldol reactions furnished the desired product. Miscellaneous thiourea-catalysts and catalytic systems promoting asymmetric transformations that lead to a six-membered ring The discovery of L-proline as an organocatalyst for the aldol reaction was of major

• importance and therefore many asymmetric reactions that could not be achieved, are now possible. There are many reactions catalyzed by L-proline, affording stereoselective products in high yields and enantiomeric excess, nevertheless there are many limitations. For that reason, it has emerged the need for

Diastereoselective Ugi reaction of chiral 1,3-aminoalcohols derived from an organocatalytic Mannich reaction

• Samantha Caputo,
• Andrea Basso,
• Lisa Moni,
• Renata Riva,
• Valeria Rocca and
• Luca Banfi

Beilstein J. Org. Chem. 2016, 12, 139–143, doi:10.3762/bjoc.12.15

• -Boc imines 2 and catalytic L-proline [29][30], followed by reduction of 3 and cleavage of the Boc group. This short and straightforward synthesis allows the introduction of 2 diversity inputs (R1 and Ar), whereas stereochemical diversity can also be explored using D-proline or different, anti

Recent advances in copper-catalyzed asymmetric coupling reactions

• Fengtao Zhou and
• Qian Cai

Beilstein J. Org. Chem. 2015, 11, 2600–2615, doi:10.3762/bjoc.11.280

• et al. [39] has been the only example of this type of catalytic asymmetric coupling reaction. They reacted 2-halotrifluoroacetanilides with 2-methylacetoacetates under the catalysis of CuI/trans-4-hydroxy-L-proline and obtained the arylated products in good yields and enantioselectivities. In this

Diversity-oriented synthesis of analogues of the novel macrocyclic peptide FR-225497 through late stage functionalization

• Jyotiprasad Mukherjee,
• Suman Sil and
• Shital Kumar Chattopadhyay

Beilstein J. Org. Chem. 2015, 11, 2487–2492, doi:10.3762/bjoc.11.270

• the trapoxins 2 and 3 contain a 2-amino-8-oxo-9,10-epoxydecanoic acid (Aoe) as the unusual amino acid. The cyclic tetrapeptide scaffold represented by structure III is nearly identical to the compounds 2–4, the difference being in the D-proline/D-pipecolic acid segment. The difference may be

Cu(I)-catalyzed N,N’-diarylation of natural diamines and polyamines with aryl iodides

• Svetlana P. Panchenko,
• Alexei D. Averin,
• Maksim V. Anokhin,
• Olga A. Maloshitskaya and
• Irina P. Beletskaya

Beilstein J. Org. Chem. 2015, 11, 2297–2305, doi:10.3762/bjoc.11.250

• of diamines and spermine while the CuI/L-proline/EtCN system proved to be preferable for the diarylation of other tri- and tetraamines like spermidine, norspermidine and norspermine. Keywords: amination; aryl amines; aryl iodides; copper catalysis; polyamines; Introduction Natural diamines and

• iodides in the copper-catalyzed amination of di- and polyamines providing mainly N-monoaryl derivatives [31]. On the basis of our recent investigations, in order to obtain N,N’-diaryl derivatives, we employed the most suitable catalytic systems, CuI/L-proline (L1) and CuI/2-(isobutyryl)cyclohexanone (L2

Recent advances in copper-catalyzed C–H bond amidation

• Jie-Ping Wan and
• Yanfeng Jing

Beilstein J. Org. Chem. 2015, 11, 2209–2222, doi:10.3762/bjoc.11.240

• of o-halobenzamides 82 and (benzo)imidazoles 87 for the one-pot synthesis of (benzo)imidazoquinazolinones 88 under the catalysis of CuI and assistance of L-proline. A subsequent oxidation using molecular oxygen was required for the final formation of products. According to the results, the mechanism

• were disclosed by Wang et al. [80]. The synthesis using 92 and benzimidazoles 87 provided benzimidazole-fused cyclic sulfonamides 93. The reaction allowed the synthesis of various products with fair to high yields with the assistance of L-proline as ligand. The expected conversion took place also in

Nitro-Grela-type complexes containing iodides – robust and selective catalysts for olefin metathesis under challenging conditions

• Andrzej Tracz,
• Mateusz Matczak,
• Katarzyna Urbaniak and
• Krzysztof Skowerski

Beilstein J. Org. Chem. 2015, 11, 1823–1832, doi:10.3762/bjoc.11.198

• . Thus, RCM with substrate 7 having one double bond terminally substituted with the phenyl ring as well as the formation of the trisubstituted heterocycle 9 proceeded better with chloride-containing catalysts. When proline derivative 10 was used, the diiodo catalysts performed better than nG but slightly

Fe(II)/Et₃N-Relay-catalyzed domino reaction of isoxazoles with imidazolium salts in the synthesis of methyl 4-imidazolylpyrrole-2-carboxylates, its ylide and betaine derivatives

• Ekaterina E. Galenko,
• Olesya A. Tomashenko,
• Alexander F. Khlebnikov,
• Mikhail S. Novikov and
• Taras L. Panikorovskii

Beilstein J. Org. Chem. 2015, 11, 1732–1740, doi:10.3762/bjoc.11.189

• complexes of pyrrole-2-carboxylic acid [23][24][25]. In some cases these complexes were prepared via dehydration of the corresponding proline complexes [25]. Substituted pyrrole-2-carboxylic acids as ligands of complexes are seldom used and are only exemplified by complexes of indole-2-carboxylic acid [26

An efficient synthesis of N-substituted 3-nitrothiophen-2-amines

• Sundaravel Vivek Kumar,
• Shanmugam Muthusubramanian,
• J. Carlos Menéndez and
• Subbu Perumal

Beilstein J. Org. Chem. 2015, 11, 1707–1712, doi:10.3762/bjoc.11.185

• , entry 5), pyridine (Table 1, entry 6), N,N-dimethylaminopyridine (DMAP, Table 1, entry 7), piperidine (Table 1, entry 8), L-proline (Table 1, entry 9), potassium carbonate (Table 1, entry 10), sodium carbonate (Table 1, entry 11) and caesium carbonate (Table 1, entry 12). After identifying potassium

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• POCl3 were mixed in a simple Teflon T-piece before entering a tubular reactor maintained at 22 °C (4.5 mL, tres = 30 s). Upon exiting this reactor the crude stream of the Vilsmeier reagent 76 was combined with a stream of amide 80 in DMF that was prepared in situ in a batch reactor from proline amide

Peptide–polymer ligands for a tandem WW-domain, an adaptive multivalent protein–protein interaction: lessons on the thermodynamic fitness of flexible ligands

• Katharina Koschek,
• Vedat Durmaz,
• Oxana Krylova,
• Marek Wieczorek,
• Shilpi Gupta,
• Martin Richter,
• Alexander Bujotzek,
• Christina Fischer,
• Rainer Haag,
• Christian Freund,
• Marcus Weber and
• Jörg Rademann

Beilstein J. Org. Chem. 2015, 11, 837–847, doi:10.3762/bjoc.11.93

• tandem WW-domain of formin-binding protein (FBP21). Polymer carriers were conjugated with 3–9 copies of the proline-rich decapeptide GPPPRGPPPR-NH2 (P1). Binding of the obtained peptide–polymer conjugates to the tandem WW-domain was investigated employing isothermal titration calorimetry (ITC) to

• ; proline-rich peptide sequences; Introduction Multivalency is a general principle in nature for increasing the affinity and specificity of ligand–receptor interactions [1]. Multivalent binding is characterized by the cooperative, over-additive enhancement of binding affinities of ligands and receptors in

• architecture connected with a flexible linker the tandem WW-domains of the protein FBP21 were selected. FBP21 is a protein component of the spliceosome, the multiprotein complex in the nucleus of cells responsible for the processing of primary RNA-transcripts. The two WW domains of FBP21 bind to proline-rich