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

• temperature to 90 °C, and a slightly higher yield was obtained (Table 1, entry 8). With L-proline as the best ligand, a further screening of the solvents revealed that increasing the polarity of the solvent had a positive effect on the reaction yield, and DMSO displayed as the best choice to promote the

• system of CuI/L-proline/K2CO3 in DMSO under microwave irradiation for 45 minutes. After determining the optimal reaction conditions, we then examined the general applicability of the process. First, the substituents of the indole moiety were explored (Table 2). Halogens (F, Cl, Br) were tolerated well

• equiv), L-proline (0.05 mmol, 5.8 mg, 0.2 equiv), and the base indicated (0.5 mmol, 2.0 equiv) in DMSO (2 mL). The vessel was degassed, refilled with argon, and sealed. The mixture was heated to the temperature indicated for the indicated time under microwave irradiation (fixed power, 30 W). After

Synthetic scope and DFT analysis of the chiral binap–gold(I) complex-catalyzed 1,3-dipolar cycloaddition of azlactones with alkenes

• María Martín-Rodríguez,
• Luis M. Castelló,
• Carmen Nájera,
• José M. Sansano,
• Olatz Larrañaga,
• Abel de Cózar and
• Fernando P. Cossío

Beilstein J. Org. Chem. 2013, 9, 2422–2433, doi:10.3762/bjoc.9.280

• -butyl acrylate is analyzed using DFT computed at M06/Lanl2dz//ONIOM(b3lyp/Lanl2dz:UFF) level. Several applications of these cycloadducts in the synthesis of new proline derivatives with a 2,5-trans-arrangement and in the preparation of complex fused polycyclic molecules are described. Keywords

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

• ][31], among them L-proline and its derivative were used as popular precursors from the pool of chiral compounds [13][14][15][18][19][20][21][22]. Herein, we report a concise diastereoselective synthesis of (8S,8aS)-5 starting from (R)-3-(tert-butyldimethylsilyloxy)glutarimide 14, a versatile building

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

• specifically cleaves at proline residues, it is unsurprising that the members of this drug class exhibit an embedded pyrrolidine ring (or mimic) and additional decoration (a nitrile or fluorinated alkyl substituent is present in order to reach into a local lipophilic pocket). One specific structural liability

The chemistry of isoindole natural products

• Klaus Speck and
• Thomas Magauer

Beilstein J. Org. Chem. 2013, 9, 2048–2078, doi:10.3762/bjoc.9.243

• basis of the structural similarity between 208 and marinopyrrole A, another secondary metabolite derived from a marine Streptomyces species [156]. The common biosynthetic precursor 206 stems from a mixed nonribosomal peptide synthetase (NRPS)/polyketide synthase (PKS) pathway. The amino acid proline is

The chemistry of amine radical cations produced by visible light photoredox catalysis

• Jie Hu,
• Jiang Wang,
• Theresa H. Nguyen and
• Nan Zheng

Beilstein J. Org. Chem. 2013, 9, 1977–2001, doi:10.3762/bjoc.9.234

• for the outcome of the reaction and proline was more effective than pyrrolidine. Additionally, to maximize the yields, the optimal rates for the two catalytic processes need to be similar. Since formation of the iminium ions is much faster than the addition of the enamine nucleophiles, higher yields

Organocatalyzed enantioselective desymmetrization of aziridines and epoxides

• Ping-An Wang

Beilstein J. Org. Chem. 2013, 9, 1677–1695, doi:10.3762/bjoc.9.192

• -aziridines are plentiful and can be found in a diverse set of privileged structures, including cinchona alkaloids-based PTCs, L-proline-derived amino alcohols, chiral phosphorous acids, chiral thioureas, chiral guanidines, and chiral 1,2,3-triazolium chlorides. But for the desymmetrization of meso-epoxides

• . Cinchona alkaloid-derived catalysts OC-12 to OC-19. The chiral phosphoric acids catalysts OC-20 and OC-21. The proposed mechanism for chiral phosphorous acid-induced enantioselctive desymmetrization of meso-aziridines (chiral PA = OC-21). L-Proline and its derivatives OC-22 to OC-27. Proposed bifunctional

Thiourea-catalyzed Diels–Alder reaction of a naphthoquinone monoketal dienophile

• Carsten S. Kramer and
• Stefan Bräse

Beilstein J. Org. Chem. 2013, 9, 1414–1418, doi:10.3762/bjoc.9.158

• ). At first, the use of MacMillan's imidazolidinone organocatalyst 6 [12] was examined, but no catalytic effect was observed (Table 2, entry 2). The usage of L-proline as a bifunctional catalyst only gave a slight improvement compared to the uncatalyzed reaction (Table 2, entry 3). Whereas the addition

C–C Bond formation catalyzed by natural gelatin and collagen proteins

• Dennis Kühbeck,
• Basab Bijayi Dhar,
• Eva-Maria Schön,
• Carlos Cativiela,
• Vicente Gotor-Fernández and
• David Díaz Díaz

Beilstein J. Org. Chem. 2013, 9, 1111–1118, doi:10.3762/bjoc.9.123

• composition of gelatin in terms of its amino acids content has been reported in several publications (arginine, glutamic acid, alanine, glycine, proline and hydroxyproline are the most abundant amino acids (ca. 10–25%)) [1], which makes the protein itself suitable for catalytic studies. The Henry (nitroaldol

• groups on the catalyst activity (e.g., Type A gelatin has ca. 78–80 millimoles of free carboxyl groups per 100 g of protein). The observations are in agreement with the examples reporting individual amino acids (e.g., alanine, proline) as catalysts for similar reactions [20][21][22][23][24][25][26][27

• case, the most common motifs in the amino acid sequence, which could be also associated with catalytic sites, are glycine-proline-X and glycine-X-hydroxyproline, where X is any other amino acid (see Supporting Information File 1). However, despite gelatin and collagen forming triple helices as a chiral

Enantioselective reduction of ketoimines promoted by easily available (S)-proline derivatives

• Martina Bonsignore,
• Maurizio Benaglia,
• Laura Raimondi,
• Manuel Orlandi and
• Giuseppe Celentano

Beilstein J. Org. Chem. 2013, 9, 633–640, doi:10.3762/bjoc.9.71

• 10.3762/bjoc.9.71 Abstract The behavior of readily synthesized and even commercially available (S)-proline derivatives, was studied in the trichlorosilane-mediated reduction of ketoimines. A small library of structurally and electronically modified chiral Lewis bases was considered; such compounds were

• involves the formation of a hydrogen-bond between the amide group of the catalyst and the substrate as a necessary element for stereocontrol (for another example of relevant N-formyl proline derivative see [12]). Also in Sun catalysts F [13][14] and sulfinamide G [15] as well as in chiral picolinamides H

• stereoselectivity of the process (right picture in Figure 3). It should be mentioned that Matsumura already in 2006 reported that trichlorosilane may be employed in the stereoselective reduction of ketones [28]. Catalytic amounts of N-formyl-α'-(2,4,6-triethylphenyl)-(S)-proline in combination with stoichiometric

A one-pot catalyst-free synthesis of functionalized pyrrolo[1,2-a]quinoxaline derivatives from benzene-1,2-diamine, acetylenedicarboxylates and ethyl bromopyruvate

• Mohammad Piltan,
• Loghman Moradi,
• Golaleh Abasi and
• Seyed Amir Zarei

Beilstein J. Org. Chem. 2013, 9, 510–515, doi:10.3762/bjoc.9.55

• ][26]. Ma and Yuan have reported the synthesis of pyrrolo[1,2-a]quinoxalin-4(5H)-ones by CuI/L-proline-catalyzed coupling of N-trifluoroacetyl-2-haloanilines with methyl pyrrole-2-carboxylates [27]. The development of more efficient methods for the preparation of these compounds is still an active

Efficient synthesis of β’-amino-α,β-unsaturated ketones

• Isabelle Abrunhosa-Thomas,
• Aurélie Plas,
• Nishanth Kandepedu,
• Pierre Chalard and
• Yves Troin

Beilstein J. Org. Chem. 2013, 9, 486–495, doi:10.3762/bjoc.9.52

• under different protocols in which the stereoselectivity of the reaction can be introduced through the use of a chiral catalyst [9][10] (Lewis acid, Brønsted acids, L-proline, Cinchona alkaloids derivatives, thioureas, etc.), or by the addition of chiral amines to α,β-unsaturated esters [11][12] or the

Efficient Cu-catalyzed base-free C–S coupling under conventional and microwave heating. A simple access to S-heterocycles and sulfides

• Silvia M. Soria-Castro and
• Alicia B. Peñéñory

Beilstein J. Org. Chem. 2013, 9, 467–475, doi:10.3762/bjoc.9.50

• -proline, benzotriazole, tetramethylethylenediamine (TMEDA), dimethylethylenediamine (DMEDA), and acetylacetone, under the optimized reaction conditions with 1,10-phenanthroline (Table 1, entry 9). These ligands, with different coordinating and structural properties, gave no positive results, and PhI was

Development of peptidomimetic ligands of Pro-Leu-Gly-NH₂ as allosteric modulators of the dopamine D₂ receptor

• Swapna Bhagwanth,
• Ram K. Mishra and
• Rodney L. Johnson

Beilstein J. Org. Chem. 2013, 9, 204–214, doi:10.3762/bjoc.9.24

• a type II β-turn. The synthetic approach to the novel highly constrained spiro-bicyclic turn mimics found in PLG peptidomimetics 27–29 relied on α-alkylaldehyde proline derivatives (34, Scheme 1) as key starting materials [44][46]. These aldehyde intermediates were obtained from L-proline via the

• highly moisture-labile oxazolidinone 30 of Seebach's “self-regeneration of chirality” methodology [47]. Stereoselective alkylation of 30 provided alkylated oxazolidinone 31 and cleavage of this N,O-acetal provided α-alkylated proline 32, which when Boc-protected gave 33. The formation of 34a and 34b was

• , wherein 31 is converted to 32, the hydrolysis of 31 was originally carried out under rigorous acidic conditions (aqueous HCl under reflux) and purification of the resulting α-alkylated proline 32 required tedious ion-exchange chromatography [47]. It was subsequently found that simply stirring a solution

Reactions of salicylaldehyde and enolates or their equivalents: versatile synthetic routes to chromane derivatives

• Ishmael B. Masesane and
• Zelalem Yibralign Desta

Beilstein J. Org. Chem. 2012, 8, 2166–2175, doi:10.3762/bjoc.8.244

• 24 in 94% yield (Scheme 9) [22]. In 2009, Shanthi and co-workers reported the use of the amino acid L-proline as a catalyst in a three component reaction of salicylaldehyde, malononitrile and indole for the synthesis of 2-aminochromene 27 in 90% yield (Scheme 10) [23] The synthesis proceeds through a

Mechanochemistry assisted asymmetric organocatalysis: A sustainable approach

• Pankaj Chauhan and
• Swapandeep Singh Chimni

Beilstein J. Org. Chem. 2012, 8, 2132–2141, doi:10.3762/bjoc.8.240

• various bioactive molecules [28]. Among different organocatalysts used for asymmetric aldol reactions, proline and its derivatives emerged as powerful catalysts for the enamine activation of donor aldehyde or ketone. Bolm’s group reported a solvent-free asymmetric organocatalytic aldol reaction under ball

• -milling conditions using L-proline (I) as catalyst (Scheme 1) [29][30]. Various five and six-membered cyclic ketones 1 were reacted with aromatic aldehydes 2 to provide anti-aldol products 3 in good to excellent yield (42–99%) and poor to high diastereoselectivity (50:50 to 99:1 dr) and moderate to

• excellent enantioselectivity (45 to >99% ee). Cyclohexanone derivatives resulted in high stereoselectivity of anti-aldol products; however, in the case of cyclopentanone poor diastereoselectivity was observed. The advantages of ball-milling technique over traditional stirring in the proline-catalysed aldol

Palladium-catalyzed C–N and C–O bond formation of N-substituted 4-bromo-7-azaindoles with amides, amines, amino acid esters and phenols

• Rajendra Surasani,
• Dipak Kalita,
• A. V. Dhanunjaya Rao and
• K. B. Chandrasekhar

Beilstein J. Org. Chem. 2012, 8, 2004–2018, doi:10.3762/bjoc.8.227

• yield of the product in 3 h (Table 6, entry 4). The catalytic system developed by us for the coupling of amino acid esters with N-protected 7-azaindoles was ineffective for L-proline (6f), L-serine (6g), and L-glutamic acid (6h) (Table 6, entries 8–10). This may be ascribed to the fact that these amino

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

• addition of enolizable aldehydes to maleimides in the original method suggested the possibility of producing chiral γ-lactams through the use of a chiral proline-like organocatalysts. In fact, Córdova and co-workers have previously established a protocol for such a process [13]. Based on this initial

Asymmetric desymmetrization of meso-diols by C₂-symmetric chiral 4-pyrrolidinopyridines

• Hartmut Schedel,
• Keizo Kan,
• Yoshihiro Ueda,
• Kenji Mishiro,
• Keisuke Yoshida,
• Takumi Furuta and
• Takeo Kawabata

Beilstein J. Org. Chem. 2012, 8, 1778–1787, doi:10.3762/bjoc.8.203

• racemic diols (s: up to 12) [8] and amino alcohol derivatives (s: up to 54) [9]. Catalyst 2, readily prepared from L-proline, could be employed for the kinetic resolution of amino alcohol derivatives (s: up to 11) [10]. Chiral PPY catalysts with dual functional side chains at C(2) and C(4) of the

• pyrrolidine ring such as 3 were prepared from trans-4-hydroxy-L-proline. These catalysts were found to be moderately effective for the asymmetric desymmetrization of meso-diols [11]. C2-Symmetric PPY-catalyst 4 was found to be effective for the chemo- and regioselective acylation of carbohydrates [12][14][16

Organocatalytic cascade aza-Michael/hemiacetal reaction between disubstituted hydrazines and α,β-unsaturated aldehydes: Highly diastereo- and enantioselective synthesis of pyrazolidine derivatives

• Zhi-Cong Geng,
• Jian Chen,
• Ning Li,
• Xiao-Fei Huang,
• Yong Zhang,
• Ya-Wen Zhang and
• Xing-Wang Wang

Beilstein J. Org. Chem. 2012, 8, 1710–1720, doi:10.3762/bjoc.8.195

• screening results are summarized in Table 3. (S)-Proline derivatives 1g–h, 1k, 1l were found to be ineffective for the reaction, because they afford only trace products after one day (Table 3, entries 1, 2, 5 and 6). Although a moderate yield was obtained with organocatalyst 1i bearing a sulfone functional

Enantioselective total synthesis of (R)-(−)-complanine

• Krystal A. D. Kamanos and
• Jonathan M. Withey

Beilstein J. Org. Chem. 2012, 8, 1695–1699, doi:10.3762/bjoc.8.192

• stepwise approach to 4. The reaction of aldehydes with nitrosobenzene in the presence of proline-derived secondary amine catalysts represents the current benchmark in organocatalytic α-oxygenation strategies [9]. A known drawback of this approach is the instability of the oxyaminated products, presumably

• owing to N–O bond lability. Recent reports suggest that this O-nitrosoaldol reaction proceeds much more cleanly with 2-nitrosotoluene than with nitrosobenzene, probably owing to the suppression of N–O bond cleavage [10]. Thus, treatment of aldehyde 3 with 2-nitrosotoluene in the presence of L-proline as

• mg, 3.33 mmol) and L-proline (115 mg, 1.00 mmol) in CHCl3 (20 mL) at 0 °C was added a solution of (5Z,8Z)-undeca-5,8-dienal (3, 1.66 g, 10.0 mmol) in CHCl3 (20 mL). Following stirring at 0 °C for 3 h, a solution of NaBH4 (570 mg, 15.0 mmol) in EtOH (30 mL) was added and the reaction mixture was

Organocatalytic tandem Michael addition reactions: A powerful access to the enantioselective synthesis of functionalized chromenes, thiochromenes and 1,2-dihydroquinolines

• Chittaranjan Bhanja,
• Satyaban Jena,
• Sabita Nayak and
• Seetaram Mohapatra

Beilstein J. Org. Chem. 2012, 8, 1668–1694, doi:10.3762/bjoc.8.191

• thiochromenes; and (3) Organocatalytic aza-Michael reactions to access functionalized 1,2-dihydroquinolines, using chiral proline and its derivatives (Figure 2), chiral bifunctional thioureas, cinchona alkaloids and other organocatalysts (Figure 3). For each reaction, the initial screening result of various

• -Michael addition followed by aza-Baylis–Hillman reaction by means of an iminium-allenamine activation strategy. Later on, the same authors [49] in 2011 reported a similar tandem reaction (abnormal Baylis–Hillman) between 2-alkynals 5 and salicylaldehyde derivatives 1 catalyzed by proline derivatives

• , thiochromene or 1,2-dihydroquinolin structural motifs. Screened chiral proline and its derivatives as organocatalysts. Rb = rubidium. Screened chiral bifunctional thiourea, its derivatives, cinchona alkaloids and other organocatalysts. Diarylprolinolether-catalyzed tandem oxa-Michael–aldol reaction reported by

Antifreeze glycopeptide diastereomers

• Lilly Nagel,
• Carsten Budke,
• Axel Dreyer,
• Thomas Koop and
• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 1657–1667, doi:10.3762/bjoc.8.190

• glycosylated with the disaccharide β-D-galactosyl-(1→3)-α-N-acetyl-D-galactosamine. In spite of the fact that all AFGPs found in arctic and antarctic fish share this structural homology, minor sequence variations occur, such as the replacement of alanine by proline [9][10] or the glycosylated threonine by

• of sequential mutations on the adsorption of such synthetic AFGP analogues onto ice surfaces, and to corroborate the molecular mechanism of antifreeze activity. Recently, we published the synthesis of monosaccharide-based AFGP analogues containing glycine, proline and serine instead of alanine

• proline replacements [5]. These peptides exhibit less antifreeze activity than monosaccharide-substituted AFGP analogues without proline residues. Peptoid glycoconjugates with carbohydrate moieties attached by CuI catalyzed azide-alkyne cycloaddition (CuAAC) were devoid of antifreeze activity [17

Synthetic studies towards bottromycin

• Stefanie Ackermann,
• Hans-Georg Lerchen,
• Dieter Häbich,
• Angelika Ullrich and
• Uli Kazmaier

Beilstein J. Org. Chem. 2012, 8, 1652–1656, doi:10.3762/bjoc.8.189

• . 3668-L2, named bottromycin A and B [13][14]. Acidic hydrolysis provided a mixture of all-(S)-configured amino acids containing 3-methylphenylalanine [15], tert-leucine, valine, β-(2-thiazolyl)-β-alanine [16] and glycine. While also proline was found in bottromycin B, cis-3-methylproline is a component

• by Schipper [20] and Kaneda [21], based on detailed NMR studies. According to them, the bottromycins are cyclic tetrapeptides, connected to a tripeptidic side chain through an amidine structure. The different bottromycins differ only in the substitution pattern of the proline (Figure 1). The three

• endothiopeptide and ring closure between proline and glycine. The same group also undertook some modifications on the natural product [26]. Results and Discussion Our group is also involved in the synthesis of peptide-based natural products [27][28][29][30][31][32], and of course the structure of bottromycin is

A quantitative approach to nucleophilic organocatalysis

• Herbert Mayr,
• Sami Lakhdar,
• Biplab Maji and
• Armin R. Ofial

Beilstein J. Org. Chem. 2012, 8, 1458–1478, doi:10.3762/bjoc.8.166

• , which leads to deprotonation of the imidazolidinium ions 1-H+ and inhibition of the formation of the iminium ions 3 (Figure 16) [64]. Enamine activated reactions When proline catalysis and related amino-acid catalyzed reactions are excluded, the catalytic cycle depicted in Figure 17 represents the

• electrophilicity scales in [4]. When proline or structurally related bifunctional catalysts are employed, the mechanism depicted in Figure 17 has to be modified. List and Houk explained the high enantioselectivity of proline catalyzed reactions of aldehydes or ketones with electrophiles by the transition state TS

• question of whether oxazolidinones, rather than being “parasitic species”, may also play a decisive role in determining the stereochemical course of proline-catalyzed reactions. In order to account for the observed stereoselectivities, it was suggested that TS-B is favored over the stereoelectronically