Asymmetric Ugi 3CR on isatin-derived ketimine: synthesis of chiral 3,3-disubstituted 3-aminooxindole derivatives

• Giordano Lesma,
• Fiorella Meneghetti,
• Alessandro Sacchetti,
• Mattia Stucchi and
• Alessandra Silvani

Beilstein J. Org. Chem. 2014, 10, 1383–1389, doi:10.3762/bjoc.10.141

• reaction of ketimine 1 in the presence of different N-Boc-protected amino acids as acid components. The use of L-amino acids 3c and 3d (Table 2, entry 8 and entry 9) afforded the desired products with moderate yields. The best result in terms of de (54%) was achieved with the more hindered proline. The

A novel family of (1-aminoalkyl)(trifluoromethyl)- and -(difluoromethyl)phosphinic acids – analogues of α-amino acids

• Natalia V. Pavlenko,
• Tatiana I. Oos,
• Yurii L. Yagupolskii,
• Igor I. Gerus,
• Uwe Doeller and
• Lothar Willms

Beilstein J. Org. Chem. 2014, 10, 722–731, doi:10.3762/bjoc.10.66

• , alanine, valine, proline, aminomalonic and aspartic acids were thus prepared. Three-component one-pot reactions of (trifluoromethyl)phosphinic acid and dibenzylamine with aldehydes were also tested to prepare the title compounds. Keywords: (1-aminoalkyl)phosphinic acids; ethyl (difluoromethyl)phosphinate

• methylphosphinic acid analogues of the protein amino acids [12] and those of glycine [13], alanine [14], valine [14], leucine [15], proline [16], aspartic [17] and glutamic [11] acids and GABA [18] have been described. But almost nothing is known about phosphorus isosters of aminocarboxylic acids bearing a

• (1) to a series of N-benzylimines 16a–e in order to obtain fluorinated phosphorus analogues of glycine 14a, phenylglycine 14b, alanine 14c, valine 14d and proline 14e (Table 1). The transformations were mildly exothermic and were monitored by 31P NMR. Acid 1 undergoes the typical P–C bond forming

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• diastereoselectivities (70–99%). In a variation, they also performed the reaction with L-aspartic acid α-peptide esters yielding endo-β-lactam mimics 29 in good yields (49–64%, de 74–98%). Five-membered ring constraints In natural peptides, the cyclic proteinogenic amino acid proline has stabilizing and turn-inducing

• properties determining the secondary and teriary structure and conformation of peptides [7][47][48]. Moreover, their influence on an altered cis/trans ratio of the amide bond has provided in-depth insights in conformation and receptor binding [49]. Thus, the specific properties of proline play a crucial role

• to determine the biological activity of peptides and peptidomimetics,[50] and research towards such peptidic structures containing proline-analogues has received much attention [48]. In this part, multicomponent reactions to access pyrrolidines and other five-membered derivatives such as γ-lactams

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

• nonsymmetric ketones. Moreover, an optical active compound could be generated during the reaction process since a chiral catalyst (proline) is used in the reactions. However, enantioselectivity was not observed by chiral HPLC analysis, and 3-pentanone gives rise to a mixture of diastereoisomers. Following this

Synthesis and stereochemical assignments of diastereomeric Ni(II) complexes of glycine Schiff base with (R)-2-(N-{2-[N-alkyl-N-(1-phenylethyl)amino]acetyl}amino)benzophenone; a case of configurationally stable stereogenic nitrogen

• Hiroki Moriwaki,
• Daniel Resch,
• Hengguang Li,
• Iwao Ojima,
• Ryosuke Takeda,
• José Luis Aceña and
• Vadim A. Soloshonok

Beilstein J. Org. Chem. 2014, 10, 442–448, doi:10.3762/bjoc.10.41

• commercial application of chiral complex 1 is rather limited. The major shortcomings of compound 1 are: problematic scale up of its synthesis, partial racemization of the N-(benzyl)proline moiety and undesirable stereochemical outcomes. To overcome these deficiencies we initiated a project aiming to design a

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

• (commercial trade names Halocur® (lactate salt) and Stenorol® (hydrobromide salt)) [22]. Other relevant examples are 3-hydroxypipecolic acids, which serve as (conformationally restricted) substitutes of proline and serine [23][24] and have been incorporated into diverse bioactive peptidomimetics [25][26], and

• ring expansions of 2-(α-hydroxyalkyl)pyrrolidines deduced to proline. 3. Based on the ring expansion of Cossy and Pardo [37], O´Brien [39] realized the synthesis of L-733,060 (80% ee). The 2-(α-hydroxyalkyl)pyrrolidine precursor was prepared from a protected pyrrolidine through sparteine-mediated

Organocatalytic asymmetric fluorination of α-chloroaldehydes involving kinetic resolution

• Kazutaka Shibatomi,
• Takuya Okimi,
• Yoshiyuki Abe,
• Akira Narayama,
• Nami Nakamura and
• Seiji Iwasa

Beilstein J. Org. Chem. 2014, 10, 323–331, doi:10.3762/bjoc.10.30

• polarimeter. α-Chloro aldehydes 2 were prepared with N-chlorosuccinimide in the presence of organocatalyst according to the procedure reported by Jørgensen [14] and were distilled before use. Racemic forms were synthesized with DL-proline catalyst, and optically active 2a was synthesized with L-prolinamide

Boron-substituted 1,3-dienes and heterodienes as key elements in multicomponent processes

• Ludovic Eberlin,
• Fabien Tripoteau,
• François Carreaux,
• Andrew Whiting and
• Bertrand Carboni

Beilstein J. Org. Chem. 2014, 10, 237–250, doi:10.3762/bjoc.10.19

• by using a chiral auxiliary (>95% de in the case of an L-proline-derived diene). Diversification on the different units, diene, dienophile and aldehyde, has been described. Concerning the maleimide material, substituent R3 did not exert any significant effect on the process. Other dienophiles have

Organobase-catalyzed three-component reactions for the synthesis of 4H-2-aminopyrans, condensed pyrans and polysubstituted benzenes

• Moustafa Sherief Moustafa,
• Saleh Mohammed Al-Mousawi,
• Maghraby Ali Selim,
• Ahmed Mohamed Mosallam and
• Mohamed Hilmy Elnagdi

Beilstein J. Org. Chem. 2014, 10, 141–149, doi:10.3762/bjoc.10.11

• -3,5-dicyanophthalic acid ester derivatives 37a–c were developed. The synthetic methods utilize one-pot reactions of acetylene carboxylic acid esters, α,β-unsaturated nitriles and/or active methylenenitriles in the presence of L-proline or DABCO. Plausible mechanisms are suggested for the formation of

• -oxo-5-phenyl-3H-isoindole-4-carboxylate (40). Keywords: aminopyranes; arylbenzoic acid; DABCO; L-proline; multicomponent; tetrahydronaphthalene; three-component reaction; Introduction The reaction of arylidenemalononitriles with active methyl and methylene compounds was extensively utilized for the

• generated using a one-pot reaction involving condensation of ethyl propiolate (4a) with benzylidenemalononitrile (7a) in the presence of L-proline (5) (Scheme 4) [4]. It is believed that the pathway followed in this process involves conjugate addition of proline to the propiolate to yield adduct 6 which

The regioselective synthesis of spirooxindolo pyrrolidines and pyrrolizidines via three-component reactions of acrylamides and aroylacrylic acids with isatins and α-amino acids

• Tatyana L. Pavlovskaya,
• Fedor G. Yaremenko,
• Victoria V. Lipson,
• Svetlana V. Shishkina,
• Oleg V. Shishkin,
• Vladimir I. Musatov and
• Alexander S. Karpenko

Beilstein J. Org. Chem. 2014, 10, 117–126, doi:10.3762/bjoc.10.8

• azomethine ylides, generated in situ via decarboxylative condensation of isatins and N-substituted α-amino acids (sarcosine, proline and thiazolidine-4-carboxilic acid) in a three-component fashion. Results and Discussion The three-component condensation of equimolar amounts of isatins 1, α-amino acids 2 and

• for proline as a substrate (Table 1, entries 1 and 3). The 1,3-dipolar cycloaddition of unsymmetrical dipolarophiles such as acrylamides can occur via the two pathways A and B leading to the formation of the regioisomers 4 and 4’. In our case, spirooxindol 4 is exclusively formed. All new cycloadducts

• dipolarophiles 5 with non-stabilized azomethine ylides generated from isatins 1 and sarcosine/proline has led to spiropyrrolidines 6a,6b and spiropyrrolizidines 6c–6h in moderate to good yields. In this reaction also two regioisomers can be expected, but in all experiments solely the regioisomer 6 is isolated

Modulating NHC catalysis with fluorine

• Yannick P. Rey and
• Ryan Gilmour

Beilstein J. Org. Chem. 2013, 9, 2812–2820, doi:10.3762/bjoc.9.316

• triazolium salts 5 and 6 [18][22]. The route to target 7 began by treating N-Boc-trans-4-hydroxy-L-proline methyl ester (11) with diethylaminosulfur trifluoride (DAST) in CH2Cl2 to install the first fluoro substituent (12) with clean configurational inversion (88%, Scheme 1). Oxidation of the pyrrolidine to

• have been omitted for clarity. An overview of the molecular editing approach to catalyst development. Synthesis of the difluorinated triazolium salt 7 starting from commercially available N-Boc-trans-4-hydroxy-L-proline methyl ester (11). Synthesis of the monofluorinated triazolium salt 8. Synthesis of

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

• example, Raines and co-workers found that (4R)-fluoroproline 12 adopts a Cγ-exo ring pucker (Figure 4), in contrast with natural proline 11 which has a more flexible pyrrolidine ring [23]. The increased rigidity of 12 was explained by a stabilising hyperconjugation phenomenon (Figure 4), in which an

• the context of organocatalysis. Fluorination of proline itself, as well as related N-heterocycles, has been shown to increase enantioselectivity in certain organocatalytic processes [13]. For example, Alexakis and co-workers found that the non-fluorinated catalyst 13 (Scheme 2) catalysed an alkylation

• influenced by a C–F…N+ charge–dipole interaction. Fluorination ridifies the pyrrolidine rings of ligand 10, with several consequences for its G-quadruplex DNA binding properties. Proline 11 readily undergoes a ring-flip process, but (4R)-fluoroproline 12 is more rigid because of hyperconjugation (σCH → σ*CF

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