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

• equivalent acid functional material can be prepared starting from tyrosine (1.78) via a dual protection of the amino acid unit as the methyl ester and the amine as the benzaldehyde imine (Scheme 14). This is then followed by analogous ether formation with the previously generated mesylate 1.74. Intermediate

Non-cross-linked polystyrene-supported 2-imidazolidinone chiral auxiliary: synthesis and application in asymmetric alkylation reactions

• Quynh Pham Bao Nguyen and
• Taek Hyeon Kim

Beilstein J. Org. Chem. 2013, 9, 2113–2119, doi:10.3762/bjoc.9.248

• . Results and Discussion First, the 2-imidazolidinone chiral auxiliary 1 was prepared in the solution phase from the commercially available O-benzyl-L-tyrosine in four steps, as previously reported [18]. For the synthesis of our envisioned homogeneous polymer, we began to directly co-polymerize a pair of

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

• subdivided into cytochalasins [41] (phenylalanine), chaetoglobosins [45][46] (tryptophan), aspochalasins [47] (leucine), pyrichalasins [48] (tyrosine) or alachalasins [49][50] (alanine). The biosynthesis of cytochalasans was established on the basis of various isotope labeling experiments using cytochalasin

• –Spengler reaction of dopamine (99) with 4-hydroxyphenylacetaldehyde (100), both derived from L-tyrosine (98) (Scheme 11). After oxidation and O-methylation, which is carried out by S-adenosylmethionine (SAM), (S)-reticuline (101) is obtained. Oxidation of the N-methyl group to the iminium ion and

• relationship between these three classes [87][96]. The biosynthesis of aristolochic acid I (117) was elucidated via labeling experiments and is depicted in Scheme 14 [97][98][99][100]. First, two molecules of the amino acid L-tyrosine (98) are transformed to (R)-orientaline (121) in a similar fashion as

Flow synthesis of a versatile fructosamine mimic and quenching studies of a fructose transport probe

• Matthew B. Plutschack,
• D. Tyler McQuade,
• Giulio Valenti and
• Peter H. Seeberger

Beilstein J. Org. Chem. 2013, 9, 2022–2027, doi:10.3762/bjoc.9.238

• that accounts for both dynamic and static quenching. Free amino acids at high concentrations can also quench fluorophores. To access the propensity for NBDM to be quenched by amino acids, we measured fluorescence in the presence of varying concentrations of alanine, glutamine, lysine, tyrosine

• , methionine and histidine. As expected, the amino acids lacking functionality known to quench fluorophores (alanine, glutamine and lysine) did not quench NBDM at concentrations as high as 50 mM. Interestingly, tyrosine did not quench NBDM fluorescence even at concentrations as high as 2 mM (solubility limit

• for tyrosine). Methionine and histidine, however, did quench NBDM via a dynamic mechanism (Figure 4). Carbohydrate–carbohydrate and carbohydrate–aromatic ring interactions are well-known [29][30]. Based on these interactions, we hypothesized that abnormal fluorescence behavior may be exhibited at high

The conjugation of nonsteroidal anti-inflammatory drugs (NSAID) to small peptides for generating multifunctional supramolecular nanofibers/hydrogels

• Jiayang Li,
• Yi Kuang,
• Junfeng Shi,
• Yuan Gao,
• Jie Zhou and
• Bing Xu

Beilstein J. Org. Chem. 2013, 9, 908–917, doi:10.3762/bjoc.9.104

• the hydrogel. Being thermally reversible and relatively sensitive to the temperature, the hydrogel of 1a exhibits excellent recovery properties (Supporting Information File 1, Figure S4) [64]. The hydrogelation of 1a also offers an opportunity to examine whether the attachment of a tyrosine phosphate

• residue to 1a allows enzymatic hydrogelation. As a soluble precursor, 1c (15.0 mg) dissolves in water (1.0 mL) at pH 7.6. After being treated with alkaline phosphatase (5.0 U/mL), the solution of 1c quickly transforms to a clear hydrogel within one hour. Due to the additional tyrosine residue, 1d, however

• ][66][67][68] that constitute the weakly cross-linked matrices of the hydrogel. The addition of a D-tyrosine phosphate residue to 1b affords the precursor 1e. Despite containing a D-tyrosine phosphate, 1e (0.8 wt %, pH 7.6) undergoes dephosphorylation in the presence of alkaline phosphatase (5.0 U/mL

Synthesis and testing of the first azobenzene mannobioside as photoswitchable ligand for the bacterial lectin FimH

• Vijayanand Chandrasekaran,
• Katharina Kolbe,
• Femke Beiroth and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2013, 9, 223–233, doi:10.3762/bjoc.9.26

• of FimH FlexX [24][25][26], flexible docking and consensus scoring [27][28], as implemented in Sybyl 6.9 [29], was employed. Docking was based on two different X-ray structures of FimH. They differ in the conformation of the so-called tyrosine gate at the entrance of the CRD, formed by the side

• chains of Y48 and Y137. One structure is crystallised in an “open-gate” conformation [9], another in the “closed-gate” conformation [10]. Affinity of any FimH ligand is improved when it exerts favourable interactions with the tyrosine gate of FimH. Thus, this substructure is an important feature of the

• the CRD of the lectin, as expected, and furthermore, that in both cases the azobenzene moiety exerts effective interactions with the tyrosine gate involving both benzene rings. Regardless of whether the (E)- or the (Z)-form of 2 is complexed with FimH, favourable π–π interactions can be formed between

Synthesis of 5-(ethylsulfonyl)-2-methoxyaniline: An important pharmacological fragment of VEGFR2 and other inhibitors

• Miroslav Murár,
• Gabriela Addová and
• Andrej Boháč

Beilstein J. Org. Chem. 2013, 9, 173–179, doi:10.3762/bjoc.9.20

• -(ethylsulfonyl)-2-methoxy-1,3-dinitrobenzene (4a) have been precisely physicochemically characterised. Keywords: angiogenesis; pharmacophoric ligand; synthesis of 5-(ethylsulfonyl)-2-methoxyaniline; VEGFR2 tyrosine kinase inhibitors; Introduction 5-(Ethylsulfonyl)-2-methoxyaniline (5) is a starting material

• . Compound 5 is used for the development of small organic compounds, i.e., modulators targeting a broad spectrum of important human protein receptors or enzymes, e.g., VEGFR2, EGFR, PDGFR, TEK kinase, ckit, EphB4, ErbB-2 receptor tyrosine kinase, cyclin-dependent kinases 2 and 4, neu receptor, polo-like

• VEGFR2 receptor has been solved by X-ray crystallography and is available in the Protein Data Bank (PDB: 1Y6A). The complex 1Y6A contains the intracellular tyrosine kinase domain of the VEGFR2 receptor, which accommodates two conformers of the AAZ ligand [5]. Compound 5 is an important precursor for the

Chemical modification allows phallotoxins and amatoxins to be used as tools in cell biology

• Jan Anderl,
• Hartmut Echner and
• Heinz Faulstich

Beilstein J. Org. Chem. 2012, 8, 2072–2084, doi:10.3762/bjoc.8.233

• protected as tert-butyl ethers (tyrosine), tert-butyloxycarbonyl derivatives (lysine), trityl derivatives (cysteine, glutamine), and as (2,2,4,6,7-pentamethyl)dihydrobenzofuran-5-sulfonyl derivative (arginine). Coupling was performed by using a 4-fold excess of each of the protected amino acids and the

Total synthesis and biological evaluation of fluorinated cryptophycins

• Christine Weiß,
• Tobias Bogner,
• Benedikt Sammet and
• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 2060–2066, doi:10.3762/bjoc.8.231

• suggests four different fragments to be assembled in the total synthesis, named unit A–D (Figure 1). Unit A is an α,β-unsaturated δ-hydroxy acid that usually also contains a benzylic epoxide or a benzylic double bond. Unit B represents a chlorinated O-methyl-D-tyrosine derivative, while unit C is a β2

• substituents at the D-tyrosine residue were crucial for high antimitotic activity [17][18]. Moore et al. patented the synthesis of fluorinated analogues of cryptophycin-1 and cryptophycin-52 [20]. In particular, derivative 3 was shown to retain biological activity (IC50 = 39 pM) and was active against the

Modulating the activity of short arginine-tryptophan containing antibacterial peptides with N-terminal metallocenoyl groups

• H. Bauke Albada,
• Alina-Iulia Chiriac,
• Michaela Wenzel,
• Maya Penkova,
• Julia E. Bandow,
• Hans-Georg Sahl and
• Nils Metzler-Nolte

Beilstein J. Org. Chem. 2012, 8, 1753–1764, doi:10.3762/bjoc.8.200

• activities of the synAMPs (MIC values) were compared to those of GS(K2Y2) (Y = D-tyrosine), a gramicidin S analogue, and vancomycin, one of the last lines of defense against Staphylococcus infections. From the antibacterial activity screening, the two most active peptides were selected for further analysis

Synthetic glycopeptides and glycoproteins with applications in biological research

• Ulrika Westerlind

Beilstein J. Org. Chem. 2012, 8, 804–818, doi:10.3762/bjoc.8.90

• tyrosine residues form the “tyrosine gate” [134]. By π–π stacking interactions with the aromatic tyrosine residues, monovalent α-mannose ligands containing hydrophobic aglycons, have shown increased binding affinities [128][135][136]. Employing multivalent ligands, the binding affinity to FimH could be

• with the FimH tyrosine gate; this effect was more pronounced by the divalent glycopeptides. In accordance with other studies, it could be concluded that the distance between the mannoside ligands was important, showing stronger inhibition for the divalent glycopeptide with a larger spatial ligand

Investigation of the network of preferred interactions in an artificial coiled-coil association using the peptide array technique

• Raheleh Rezaei Araghi,
• Carsten C. Mahrenholz,
• Rudolf Volkmer and
• Beate Koksch

Beilstein J. Org. Chem. 2012, 8, 640–649, doi:10.3762/bjoc.8.71

• single hydrophobic position with tyrosine (L15Y) in the YaLdEeEg mutant results in a significant reduction in the spot intensity compared to that of wt Acid-pp. As already discussed, despite the similarity in size between Phe and Tyr residues, they exhibit prominent differences in the coiled-coil

Enantioselective supramolecular devices in the gas phase. Resorcin[4]arene as a model system

• Caterina Fraschetti,
• Matthias C. Letzel,
• Antonello Filippi,
• Maurizio Speranza and
• Jochen Mattay

Beilstein J. Org. Chem. 2012, 8, 539–550, doi:10.3762/bjoc.8.62

• this purpose, the proton-bonded diastereomeric [V∙H∙G]+ complexes [G = tyrosine methyl ester (tyrOMe), and amphetamine (amph); Figure 7] were generated in the ESI source of an FT-ICR-MS to measure the kinetics of their ligand displacement towards the enantiomers of the neutral 2-aminobutane (B) (Table

Aldol elaboration of 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridin-4-ones, masked precursors to acylpyridones

• Raymond C. F. Jones,
• Abdul K. Choudhury,
• James N. Iley,
• Mark E. Light,
• Georgia Loizou and
• Terence A. Pillainayagam

Beilstein J. Org. Chem. 2012, 8, 308–312, doi:10.3762/bjoc.8.33

• (Figure 1) is the common structural unit of a family of natural products with a range of interesting biological activities [1]. Examples are the pigments tenellin (2a) and bassianin (2b) from insect pathogenic fungus Beauveria bassiana [2][3], pyridovericin (2c) [4] (a tyrosine kinase inhibitor) and the

Thermodynamic and kinetic stabilization of divanadate in the monovanadate/divanadate equilibrium using a Zn-cyclene derivative: Towards a simple ATP synthase model

• Hanno Sell,
• Anika Gehl,
• Frank D. Sönnichsen and
• Rainer Herges

Beilstein J. Org. Chem. 2012, 8, 81–89, doi:10.3762/bjoc.8.8

• tyrosine phosphatase, this role is taken by hydrogen bonding of the phosphate ion to the positively charged arginine side chain [11]. In the key step of the hydrolysis of pyrophosphate by the yeast phosphatase, two Mg2+ ions and arginine H-bonds assist the P–O bond cleavage [12]. A number of artificial

Natural product biosyntheses in cyanobacteria: A treasure trove of unique enzymes

• Jan-Christoph Kehr,
• Douglas Gatte Picchi and
• Elke Dittmann

Beilstein J. Org. Chem. 2011, 7, 1622–1635, doi:10.3762/bjoc.7.191

• amino acid biosynthesis [70]. The biosynthetic route was proposed to start with tryptophan and tyrosine. Two of the initial steps of the sunscreen synthesis were reproduced in vitro [71]. The ORF NpR1275 was confirmed to act as a tryptophan dehydrogenase, whereas p-hydroxyphenylpyruvic acid was proposed

Chimeric self-sufficient P450cam-RhFRed biocatalysts with broad substrate scope

• Aélig Robin,
• Valentin Köhler,
• Alison Jones,
• Afruja Ali,
• Paul P. Kelly,
• Elaine O'Reilly,
• Nicholas J. Turner and
• Sabine L. Flitsch

Beilstein J. Org. Chem. 2011, 7, 1494–1498, doi:10.3762/bjoc.7.173

• specificity of P450cam can be significantly broadened by specific mutations, in particular by mutating the tyrosine residue at position 96 (Y96) in combination with other sites such as V247 [15][16][17][18][19][20][21][22]. Exchanging Y96 for an alanine residue allows the oxidation of unnatural substrates

A novel high-yield synthesis of aminoacyl p-nitroanilines and aminoacyl 7-amino-4-methylcoumarins: Important synthons for the synthesis of chromogenic/fluorogenic protease substrates

• Xinghua Wu,
• Yu Chen,
• Herve Aloysius and
• Longqin Hu

Beilstein J. Org. Chem. 2011, 7, 1030–1035, doi:10.3762/bjoc.7.117

• removal of the Boc protecting group and oxidation of the free amino group to the nitro group [13]. This method, however, is not applicable to methionine, tyrosine, tryptophan and cysteine, all of which are sensitive to the oxidation conditions used. As an alternative, Nα-protected amino acids were used to

• obtained. We also found that the hydroxy group of tyrosine and threonine did not need to be protected. No significant intermolecular esterification was observed under the present reaction conditions and the desired p-nitroanilides were obtained in excellent yields (Table 1, entries 2 and 3). Furthermore

Photoinduced electron-transfer chemistry of the bielectrophoric N-phthaloyl derivatives of the amino acids tyrosine, histidine and tryptophan

• Axel G. Griesbeck,
• Jörg Neudörfl and
• Alan de Kiff

Beilstein J. Org. Chem. 2011, 7, 518–524, doi:10.3762/bjoc.7.60

• Axel G. Griesbeck Jorg Neudorfl Alan de Kiff University of Cologne, Department of Chemistry, Organic Chemistry, Greinstr. 4, D-50939 Köln, Germany; Fax: +49(221)470 5057 10.3762/bjoc.7.60 Abstract The photochemistry of phthalimide derivatives of the electron-rich amino acids tyrosine, histidine

• and tryptophan 8–10 was studied with respect to photoinduced electron-transfer (PET) induced decarboxylation and Norrish II bond cleavage. Whereas exclusive photodecarboxylation of the tyrosine substrate 8 was observed, the histidine compound 9 resulted in a mixture of histamine and preferential

• cysteine and S-methyl cysteine derivatives [8]. Other proteinogenic amino acids that, in principle, should also be able to show bielectrophoric behavior with aromatic side chains similar to phenylalanine are tyrosine, histidine and tryptophan. The photochemistry of the phthalimide derivatives of these

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• atorvastatin structure was then obtained in only three additional steps via acetal cleavage, ester hydrolysis and formation of the calcium salt. Sunitinib (36, Sutent) is Pfizer’s novel receptor tyrosine kinase inhibitor (RTK) approved in 2006 by the FDA for the treatment of both renal cell carcinoma and

• normally filled by the ADP’s adenine in the phosphorylated protein. The indolinone section is located in a deeper pocket with the heteroatoms being involved in H-bonding glutamate and tyrosine residues whilst the pyrrole ring and the diethylaminoethyl appendage are exposed to the solvent environment [8

• . Indazole Pazopanib (246, Votrient) is a new potent multi-target tyrosine kinase inhibitor for various human cancer cell lines. Pazopanib is considered a promising replacement treatment to imatinib and sunitinib and was approved for renal cell carcinoma by the FDA in late 2009. The indazole system is built

C–C (alkynylation) vs C–O (ether) bond formation under Pd/C–Cu catalysis: synthesis and pharmacological evaluation of 4-alkynylthieno[2,3-d]pyrimidines

• Dhilli Rao Gorja,
• K. Shiva Kumar,
• K. Mukkanti and
• Manojit Pal

Beilstein J. Org. Chem. 2011, 7, 338–345, doi:10.3762/bjoc.7.44

• ., alkynyl substituted thienopyrimidines of potential pharmacological interest. Notably, 6-ethynylthieno[3,2-d]- and 6-ethynylthieno[2,3-d]pyrimidin-4-aniline derivatives were found to be potent inhibitors of ErbB family receptor tyrosine kinases (EGFR, ErbB-2) and the proliferation of tumor cells that

A two step synthesis of a key unit B precursor of cryptophycins by asymmetric hydrogenation

• Benedikt Sammet,
• Mathilde Brax and
• Norbert Sewald

Beilstein J. Org. Chem. 2011, 7, 243–245, doi:10.3762/bjoc.7.32

• interacting with the β-subunit of α/β-tubulin heterodimers. Numerous natural and artificial analogs have been analysed in structure–activity relationship (SAR) studies. The unit B of cryptophycins contains a considerably modified D-tyrosine derivative (Figure 1). Substituent variations at unit B are not well

• tolerated. Both the methoxy and the chloro substituent are required for full biological activity [1][2][3][4]. The previously published synthetic route to unit B precursor 4 involves a three-step modification of D-tyrosine by chlorination, protecting group introduction and double methylation followed by a

• final saponification reaction to give carboxylic acid 5 (Scheme 1). A number of experimental procedures for this route have been published [5][6][7]. The selective monochlorination of D-tyrosine is quite cumbersome since the formation of the dichlorinated product must be minimized and the presence of

Application of the diastereoselective photodeconjugation of α,β-unsaturated esters to the synthesis of gymnastatin H

• Ludovic Raffier and
• Olivier Piva

Beilstein J. Org. Chem. 2011, 7, 151–155, doi:10.3762/bjoc.7.21

• , gymnastatins 10 constitute a family of compounds isolated from Gymnascella dankaliensis which grows in symbiosis with the marine sponge Halichondria japonica [10] (Figure 2). Gymnastatins 10 possess a common unsaturated fatty acid residue connected to a tyrosine subunit. These compounds have been reported to

• ) configuration at the C-6 carbon. By saponification under mild conditions, 24 was converted into carboxylic acid 25 which was implicated into a free-epimerising amidation procedure with HOBt [22] and the readily available O-protected tyrosine derivative 26. Finally, the TBS group of the amino ester moiety was

En route to photoaffinity labeling of the bacterial lectin FimH

• Thisbe K. Lindhorst,
• Michaela Märten,
• Andreas Fuchs and
• Stefan D. Knight

Beilstein J. Org. Chem. 2010, 6, 810–822, doi:10.3762/bjoc.6.91

• CRD was taken as the lead structure for the design of an appropriate photoactive ligand. Inspection of the available X-ray data clearly shows that α-D-mannosides are complexed in the CRD with the aglycone moiety sticking out of the binding pocket. The entrance of the CRD is flanked by the tyrosine

• residues Tyr48 and Tyr137 (‘tyrosine gate’) that can form favorable interactions with appropriate mannosidic aglycone moieties, such as π-π-stacking with the phenyl group of benzyl mannosides [14]. In a preceding work, we synthesized the three corresponding photoactive α-D-mannosides, 1, 2, and 3 (Figure

• of its free binding energy. Low (more negative) scores correlate with high affinities, whilst higher scores reflect diminished binding potency (Table 1). Docking was based on two different X-ray structures. In the first case, crystals with an open tyrosine gate were taken as the basis [7], whilst in

Molecular recognition of organic ammonium ions in solution using synthetic receptors

• Andreas Späth and
• Burkhard König

Beilstein J. Org. Chem. 2010, 6, No. 32, doi:10.3762/bjoc.6.32

• and enantiomeric selectivities were obtained for the R-enantiomers of tyrosine and its potassium salt. The more pronounced enantioselectivity of tyrosine may be explained by hydrogen bonding and the favorable π–π interaction between the hosts’ side arm and the aromatic moiety of guests. The higher