cas 59936-29-7, Boc-L-Proline-methyl ester

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METHODS OF TREATING PAINFUL DIABETIC PERIPHERAL NEUROPATHY
Provided herein are methods of treating painful diabetic peripheral neuropathy, such as advanced painful DPN, in a patient by administering to the patient an effective amount of NYX-2925 or a pharmaceutically acceptable salt thereof. Also provided are crystalline forms of 3-hydroxy-2-(5-isobutyryl-1-oxo-2,5-diazaspiro[3,4]octan-2-yl)butanamide.
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(2021/05/14)

X-ray Structure-Guided Discovery of a Potent, Orally Bioavailable, Dual Human Indoleamine/Tryptophan 2,3-Dioxygenase (hIDO/hTDO) Inhibitor That Shows Activity in a Mouse Model of Parkinson’s Disease
Human indoleamine 2,3-dioxygenase 1 (hIDO1) and tryptophan 2,3-dioxygenase (hTDO) have been closely linked to the pathogenesis of Parkinson’s disease (PD); nevertheless, development of dual hIDO1 and hTDO inhibitors to evaluate their potential efficacy against PD is still lacking. Here, we report biochemical, biophysical, and computational analyses revealing that 1H-indazole-4-amines inhibit both hIDO1 and hTDO by a mechanism involving direct coordination with the heme ferrous and ferric states. Crystal structure-guided optimization led to23, which manifested IC50values of 0.64 and 0.04 μM to hIDO1 and hTDO, respectively, and had good pharmacokinetic properties and brain penetration in mice.23showed efficacy against the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse motor coordination deficits, comparable to Madopar, an anti-PD medicine. Further studies revealed that different from Madopar,23likely has specific anti-PD mechanisms involving lowering IDO1 expression, alleviating dopaminergic neurodegeneration, reducing inflammatory cytokines and quinolinic acid in mouse brain, and increasing kynurenic acid in mouse blood.
Ning, Xiang-Li,Li, Yu-Zhi,Huo, Cui,Deng, Ji,Gao, Cheng,Zhu, Kai-Rong,Wang, Miao,Wu, Yu-Xiang,Yu, Jun-Lin,Ren, Ya-Li,Luo, Zong-Yuan,Li, Gen,Chen, Yang,Wang, Si-Yao,Peng, Cheng,Yang, Ling-Ling,Wang, Zhou-Yu,Wu, Yong,Qian, Shan,Li, Guo-Bo
p. 8303 - 8332
(2021/06/30)

Tetrahydropyrido [3, 4-d] pyrimidine derivative and medical application thereof
The invention relates to a compound as shown in a general formula (I) or a stereoisomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or eutectic crystal thereof, an intermediate and a preparation method thereof, and application of the compound in preparation of drugs for treating diseases related to KRas-G12C activity or expression quantity.
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Paragraph 0273; 0277; 0319-0323

(2021/03/06)

METHODS OF TREATING FIBROMYALGIA
Provided herein are methods of treating fibromyalgia, in a patient by administering to the patient an effective amount of NYX-2925 or a pharmaceutically acceptable salt thereof.
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Paragraph 0267; 0271-0273

(2021/10/11)

Direct Amidation of Esters by Ball Milling**
The direct mechanochemical amidation of esters by ball milling is described. The operationally simple procedure requires an ester, an amine, and substoichiometric KOtBu and was used to prepare a large and diverse library of 78 amide structures with modest to excellent efficiency. Heteroaromatic and heterocyclic components are specifically shown to be amenable to this mechanochemical protocol. This direct synthesis platform has been applied to the synthesis of active pharmaceutical ingredients (APIs) and agrochemicals as well as the gram-scale synthesis of an active pharmaceutical, all in the absence of a reaction solvent.
Nicholson, William I.,Barreteau, Fabien,Leitch, Jamie A.,Payne, Riley,Priestley, Ian,Godineau, Edouard,Battilocchio, Claudio,Browne, Duncan L.
supporting information
p. 21868 - 21874
(2021/09/02)

Synthesis and photophysics of benzazole based triazoles with amino acid-derived pendant units. Multiparametric optical sensors for BSA and CT-DNA in solution
Herein we report the synthesis of a series of amino acid-derived triazoles by an organocatalytic cycloaddition reaction between azides and carbonyl compounds, catalyzed by a simple amine. These compounds present absorption maxima located in the UV-B ascribed to fully spin and symmetry allowed electronic transitions and a main fluorescence emission in the UV-A (~380 nm) with a relatively large Stokes shift (5700 cm?1). No significant solvatochromism was observed in both ground and excited states. Unexpectedly, the benzoxazole derivatives presented much higher fluorescence quantum yield values (40–80%) of compared to the sulfur analogues (3–6%). In addition, the DNA binding assays indicated that these compounds presented strong interaction with CT-DNA, which could be attributed to π-stacking and intermolecular hydrogen-bonding. The interaction of the benzazoles with bovine serum albumin (BSA) was also investigated, where a suppression mechanism was observed. In each case, docking was performed to better understand the observed interactions.
Debia, Natalí P.,Rodríguez, Juan J.P.,da Silveira, Carolina H.,Chaves, Otavio A.,Iglesias, Bernardo A.,Rodembusch, Fabiano S.,Lüdtke, Diogo S.
(2020/04/27)

Chiral binaphthalene-aza-polycyclic ligand and preparation method thereof
The invention discloses a chiral binaphthalene aza-polycyclic ligand and a preparation method thereof. The ligand has the following structure. The preparation method comprises the following steps: (1)by taking 1, 1 '-binaphthalene 2, 2'-diphenol as a raw material, carrying out methyl protection, Tf2O protection, methylation, aromatic ring substitution and bromination reaction to obtain a 2-bromomethyl -2'-methoxy 1, 1'-binaphthalene derivative (compound V); (2) starting from aza-polycyclic carboxylic acids such as L -or D-proline, L -or D-2-piperidinecarboxylic acid, L- or D-acridine -acid and the like, carrying out derivatization to obtain various amino alcohols (compounds B); and (3) coupling the compound V and the compound B under an alkaline condition and a catalyst, and removing a protecting group to obtain the binaphthalene aza-polycyclic chiral ligand L. The ligand has central chirality and axial chirality at the same time, and can obtain higher reaction activity and enantioselectivity in asymmetric catalytic reaction. The ligands are simple to prepare, raw materials are easy to obtain, and the ligands have important significance for asymmetric synthesis.
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(2021/01/11)

Synthesis process of chiral catalyst
The invention relates to a low-cost efficient synthesis process of both a chiral catalyst chiral (R)-(+)-2-(Diphenylhydroxymethyl)pyrrolidine and a hydrochloride thereof. According to the process, rawmaterials which can be commercially obtained easily and are environmentally friendly are used; a one-kettle method is used for operation; through esterification reaction, Boc protecting group addition on amino group, Grignard reaction and Boc protecting group removal, high-optical-purity (R)-(+)-2-(Diphenylhydroxymethyl)pyrrolidine hydrochloride is obtained. The process is simplified; the production cost is reduced; the requirements of green chemistry at present are met. The content of (R)-(+)-2-(Diphenylhydroxymethyl)pyrrolidine and the hydrochloride thereof, prepared by the process, is higher than 99.0 percent; the optical purity is not smaller than 99.5 percent; the total yield is higher than 80 percent.
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Paragraph 0090; 0091; 0093; 0096; 0098; 0102; 0104

(2019/02/17)

Novel chiral amine oxide ligand and preparation method thereof
The invention provides a novel chiral amine oxide ligand and a preparation method thereof. The method uses a simple amino acid or an amino acid derivative as a raw material, the raw material is modified, the modified material reacts with substances such as a coupling agent and an alkali, and therefore the pincher configuration chiral ligand compound is obtained, that is, the chiral amine oxide ligand. The chiral amine oxide ligand provided by the invention has a structure of a non-simple linear chain, has a soft skeleton in the molecular structure, contains a recognition gene containing heteroatoms such as oxygen or nitrogen, and can well coordinate with a series of metals and realize high enantioselectivity and high reactivity in a non-symmetric reaction; and the preparation method is simple, the steps are few, and the raw materials are cheap and easy to obtain.
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(2019/05/15)

SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF
Disclosed are compounds having potency in the modulation of NMDA receptor activity. Such compounds can be used in the treatment of conditions such as depression and related disorders as well as other disorders.
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(2019/08/26)

Unlocking the potential of phenacyl protecting groups: CO2-based formation and photocatalytic release of caged amines
Orthogonal protection and deprotection of amines remain important tools in synthetic design as well as in chemical biology and material research applications. A robust, highly efficient, and sustainable method for the formation of phenacyl-based carbamate esters was developed using CO2 for the in situ preparation of the intermediate carbamates. Our mild and broadly applicable protocol allows for the formation of phenacyl urethanes of anilines, primary amines, including amino acids, and secondary amines in high to excellent yields. Moreover, we demonstrate the utility by a mild and convenient photocatalytic deprotection protocol using visible light. A key feature of the [Ru(bpy)3](PF6)2-catalyzed method is the use of ascorbic acid as reductive quencher in a neutral, buffered, two-phase acetonitrile/water mixture, granting fast and highly selective deprotection for all presented examples.
Speckmeier, Elisabeth,Klimkait, Michael,Zeitler, Kirsten
p. 3738 - 3745
(2018/04/14)

SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF
Disclosed are compounds having potency in the modulation of NMDA receptor activity. Such compounds can be used in the treatment of conditions such as depression and related disorders. Orally delivered formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
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(2018/03/28)

Organocatalytic Nitroaldol Reaction Associated with Deuterium-Labeling
A deuterium-labeling reaction of nitroalkanes in deuterium oxide and the subsequent nitroaldol reaction have been accomplished under basic and organocatalytic conditions to provide the deuterium-labeled β-nitroalcohols in high yields and high deuterium contents. β-Deuterated β-nitroalcohols could be smoothly obtained from the reaction of nitroalkanes and various electrophiles using the easily-removal basic resin WA30. Furthermore, the asymmetric nitroaldol reaction using nitromethane and α-keto esters as electrophiles in the presence of a quinine-derived organocatalyst in deuterium oxide could provide the desired β-deuterated nitroalcohol derivatives with high enantioselectivities. (Figure presented.).
Yamada, Tsuyoshi,Kuwata, Marina,Takakura, Ryoya,Monguchi, Yasunari,Sajiki, Hironao,Sawama, Yoshinari
supporting information
p. 637 - 641
(2017/12/13)

Prolinamides of Aminouracils, Organocatalyst Modifiable by Complementary Modules
We report the synthesis and evaluation of prolinamide organocatalysts that incorporate aminouracils. The features of these catalysts are enhanced NH acidity of the amide because of the electron-withdrawing nature of the heterocycle, an additional hydrogen-bond donor at the α or β positions of this functional group (using 6-aminouracil or 5,6-diaminouracil respectively), and it can be recovered due to its low solubility and used again without decreasing the enantioselectivity. A unique feature of these systems is the self-assembly capability with complementary modules by Watson–Crick interactions. These supramolecular adducts behave differently from the catalyst alone, some of them have lower performance but others improve the selectivity of the product. Therefore, this approach avoids the synthesis of many catalysts.
Ruíz-Pérez, Karen M.,Quiroz-García, Beatriz,Hernández-Rodríguez, Marcos
supporting information
p. 5763 - 5772
(2018/11/10)

NITROGEN RING LINKED DEOXYURIDINE TRIPHOSPHATASE INHIBITORS
Provided herein are dUTPase inhibitors, compositions comprising such compounds and methods of using such compounds and compositions.
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Paragraph 0682

(2018/06/12)

New reagent for the introduction of Boc protecting group to amines: Boc-OASUD
A new reagent, tert-butyl (2,4-dioxo-3-azaspiro [5,5] undecan-3-yl) carbonate (Boc-OASUD) for the preparation of N-Boc-amino acids is described. The Boc-OASUD reacts with amino acids and their esters at room temperature in the presence of a base and gives N-Boc-amino acids and their esters in good yields and purity. Introduction of the Boc group takes place without racemization. The Boc-OASUD, being a solid and more stable, is a better alternative to di-tert-butyl dicarbonate which is low melting and has to be dispensed in plastic containers than glass because of its poor stability.
Maheswara Rao, B. Leela,Nowshuddin, Shaik,Jha, Anjali,Divi, Murali K.,Rao
supporting information
p. 2127 - 2132
(2017/10/31)

Novel reversible methionine aminopeptidase-2 (MetAP-2) inhibitors based on purine and related bicyclic templates
The natural product fumagillin 1 and derivatives like TNP-470 2 or beloranib 3 bind to methionine aminopeptidase 2 (MetAP-2) irreversibly. This enzyme is critical for protein maturation and plays a key role in angiogenesis. In this paper we describe the synthesis, MetAP-2 binding affinity and structural analysis of reversible MetAP-2 inhibitors. Optimization of enzymatic activity of screening hit 10 (IC50: 1?μM) led to the most potent compound 27 (IC50: 0.038?μM), with a concomitant improvement in LLE from 2.1 to 4.2. Structural analysis of these MetAP-2 inhibitors revealed an unprecedented conformation of the His339 side-chain imidazole ring being co-planar sandwiched between the imidazole of His331 and the aryl-ether moiety, which is bound to the purine scaffold. Systematic alteration and reduction of H-bonding capability of this metal binding moiety induced an unexpected 180° flip for the triazolo[1,5-a]pyrimdine bicyclic template.
Heinrich, Timo,Buchstaller, Hans-Peter,Cezanne, Bertram,Rohdich, Felix,Bomke, J?rg,Friese-Hamim, Manja,Krier, Mireille,Kn?chel, Thorsten,Musil, Djordje,Leuthner, Birgitta,Zenke, Frank
p. 551 - 556
(2017/01/17)

HETEROAROMATIC NMDA RECEPTOR MODULATORS AND USES THEREOF
Disclosed herein, in part, are heteroaromatic compounds and methods of use in treating neuropsychiatric disorders, e.g., schizophrenia and major depressive disorder. Pharmaceutical compositions and methods of making heteroaromatic compounds are provided. The compounds are contemplated modulate the NMDA receptor.
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(2017/07/27)

Design, synthesis, and evaluation of novel Akt1 inhibitors based on an indole scaffold
A new series of potential Akt1 inhibitors with indole scaffold were designed and synthesized. The antiproliferative activity against PC-3 cell line and enzyme inhibitory activity against Akt1 were evaluated. Among them, some compounds showed much more potent antiproliferative activity and stronger Akt1 inhibitory activity compared to the positive control of GSK690693. In particular, compound 19b exhibited the most potent inhibitory activity against Akt1 with inhibition rate of 70.3% at a concentration of 10?nm. Furthermore, compound 19b could dose dependently reduce the phosphorylation of the downstream GSK3β protein in the PC-3 cell line and displayed fivefold higher antiproliferative activity against PC-3 cell line with IC50 value of 3.1?±?0.1?μm than positive control (15.5?±?0.4?μm). Herein, compound 19b may serve as a promising lead for further optimization and development of novel Akt1 inhibitors based on an indole scaffold.
Yang, Dezhi,Tong, Dongdong,Zhang, Qian,Wang, Yongtao,Sun, Jing,Zhang, Fenghe,Zhao, Guisen
p. 791 - 803
(2017/09/30)

Aluminium, gallium and indium complexes supported by a chiral phenolato-prolinolato dianionic ligand
Congeneric complexes (S)-{?O}MCH2SiMe3 (M=Al, 3; Ga, 5; In, 6) of the triel metals supported by an enantiomerically pure phenolato-alkoxo {?O}2- dianionic tridentate ligand derived from prolinol, along with their chloro derivatives, have been prepared and characterised. The aluminium-alkyl species (S)-{?O}AlMe and 3 form four-coordinate complexes with slightly distorted tetrahedral geometries, whereas the geometry in the Lewis acidic five-coordinate (S)-{?O}GaCl·THF is a distorted trigonal bipyramid. These alkyl complexes do not react cleanly, if at all, with protic sources. The indium(III) compound 6, which is for instance inert towards iPrOH or BnOH even after hours at 70°C, catalyses at 95°C the controlled, immortal ring-opening polymerisation of racemic lactide (up to 1000 equivalents) in the presence of excess BnOH as a chain transfer agent. It affords atactic, monodisperse polylactides with predictable molecular weights.
Maudoux, Nicolas,Tan, Eric,Hu, Yuya,Roisnel, Thierry,Dorcet, Vincent,Carpentier, Jean-Fran?ois,Sarazin, Yann
p. 131 - 143
(2016/12/14)

Pyrrolidine modified PANF catalyst for asymmetric Michael addition of ketones to nitrostyrenes in aqueous phase
Three chiral pyrrolidine functionalized polyacrylonitrile fiber catalysts have been designed, prepared, and evaluated for their catalytic performance in asymmetric Michael addition of ketones to nitrostyrenes in water. With the optimized catalysts and conditions in hand, their reaction scope for nitrostyrenes was explored. Then the fiber catalysts were further applied to a packed-bed reactor for continuous-flow Michael addition. Based on the fact that organic solvent can inhibit the catalytic activity, a novel microenvironment catalytic mechanism is proposed.
Du, Jianguo,Shuai, Bin,Tao, Minli,Wang, Guangwei,Zhang, Wenqin
supporting information
p. 2625 - 2631
(2016/05/24)

(S)-1,1-diphenylprolinol trimethylsilyl ether
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Boeckman, Robert K.,Tusch, Douglas J.,Biegasiewicz, Kyle F.
p. 309 - 319
(2016/08/23)

A systematic approach to diverse, lead-like scaffolds from α,α-disubstituted amino acids
A powerful strategy for the efficient lead-oriented synthesis of novel molecular scaffolds is demonstrated. Twenty two scaffolds were prepared from just four α-amino acid-derived building blocks and a toolkit of six connective reactions. Importantly, each individual scaffold has the ability to specifically target lead-like chemical space.
Foley, Daniel J.,Doveston, Richard G.,Churcher, Ian,Nelson, Adam,Marsden, Stephen P.
supporting information
p. 11174 - 11177
(2015/07/07)

Organocatalytic enantioselective α-hydroxymethylation of aldehydes: Mechanistic aspects and optimization
Further studies of the direct enantioselective α-hydroxymethylation of aldehydes employing the α,α-diarylprolinol trimethylsilyl ether class of organocatalysts are described. This process has proven efficient for access to β-hydroxycarboxylic acids and δ-hydroxy-α,β-unsaturated esters from aldehydes in generally good yields, excellent enantioselectivity, and compatibility with a broad range of functional groups in the aldehyde. The goal of these studies was to identify the critical reaction variables that influence the yield and enantioselectivity of the α-hydroxymethylation process such as catalyst structure, pH of the medium, purity of the reactants and reagents particularly with respect to the presence of acidic impurities, and the nature of the buffer, along with the standard variables including solvent, time, temperature and mixing efficiency. The previously identified intermediate lactol has been further characterized and its reactivity examined. These studies have led to identification of the most critical variables translating directly into improved substrate scope, reproducibility, enantioselectivity, and yields.
Boeckman, Robert K.,Biegasiewicz, Kyle F.,Tusch, Douglas J.,Miller, John R.
p. 4030 - 4045
(2015/05/05)

Catalytic Asymmetric Hydrogenation of Heteroarenes and Arenes
A trans-chelating chiral bisphosphine, PhTRAP, allows the ruthenium-catalyzed hydrogenation of various azoles to proceed with high enantioselectivity. The PhTRAP-ruthenium catalyst transformed indoles, pyrroles, imidazoles, and oxazoles into the correspon
Kuwano, Ryoichi
p. 715 - 719
(2016/01/15)

Aerobic Copper-Catalyzed O-Methylation with Methylboronic Acid
The oxidative coupling of alkylboronic acids with oxygen nucleophiles offers a strategy for replacing toxic, electrophilic alkylating reagents. Although the Chan-Lam reaction has been widely applied in the arylation of heteroatom nucleophiles, O-alkylation with boronic acids is rare. We report a Cu-catalyzed nondecarboxylative methylation of carboxylic acids with methylboronic acid that proceeds in air with no additional oxidant. An isotope-labeling study supports an oxidative cross-coupling mechanism, in analogy to that proposed for Chan-Lam arylation.
Jacobson, Clare E.,Martinez-Mu?oz, Noelia,Gorin, David J.
p. 7305 - 7310
(2015/07/28)

SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF
Disclosed are compounds having enhanced potency in the modulation of NMD A receptor activity. Such compounds are contemplated for use in the treatment of conditions such as depression and related disorders. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
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(2014/08/19)

SPIRO-LACTAM NMDA RECEPTOR MODULATORS AND USES THEREOF
Disclosed are compounds having enhanced potency in the modulation of NMD A receptor activity. Such compounds are contemplated for use in the treatment of conditions such as depression and related disorders. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
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(2014/08/19)

Solventless mechanosynthesis of N-protected amino esters
Mechanochemical derivatizations of N- or C-protected amino acids were performed in a ball mill under solvent-free conditions. A vibrational ball mill was used for the preparation of N-protected α- and β-amino esters starting from the corresponding N-unmasked precursors via a carbamoylation reaction in the presence of di-tert-butyl dicarbonate (Boc2O), benzyl chloroformate (Z-Cl) or 9-fluorenylmethoxycarbonyl chloroformate (Fmoc-Cl). A planetary ball mill proved to be more suitable for the synthesis of amino esters from N-protected amino acids via a one-pot activation/esterification reaction in the presence of various dialkyl dicarbonates or chloroformates. The spot-to-spot reactions were straightforward, leading to the final products in reduced reaction times with improved yields and simplified work-up procedures.
Konnert, Laure,Lamaty, Frederic,Martinez, Jean,Colacino, Evelina
p. 4008 - 4017
(2014/05/20)

Contiguous generation of quaternary and tertiary stereocenters: One-pot synthesis of chroman-fused S-proline-derived chiral oxazepinones
A new class of chroman-fused S-proline-derived chiral oxazepinones has been synthesized in one pot through contiguous generation of quaternary and tertiary stereocenters.
Singh, Ritesh,Parai, Maloy Kumar,Mondal, Sankalan,Panda, Gautam
p. 253 - 259
(2013/01/15)

A novel organocatalyst for direct asymmetric Michael additions of cyclohexanone to nitroolefins
A novel catalyst combining pyrrolidinyl and cyclohexanediamine was designed and synthesized. Only 5 mol% of catalyst loading was required for enantioselective Michael additions of cyclohexanone and nitroolefins affording desired γ-nitroketones with > 99%
Zhong, Jun,Guan, Zhi,He, Yan-Hong
p. 18 - 22
(2013/03/28)

An eco-friendly asymmetric organocatalytic conjugate addition of malonates to α,β-unsaturated aldehydes: Application on the synthesis of chiral indoles
The asymmetric Michael addition of malonates to α,β-unsaturated aldehydes using a modified Jorgensen-Hayashi organocatalyst in EtOH:brine solvent media is reported. The procedure proceeds smoothly to afford the corresponding Michael adducts in good yields with excellent enantioselectivities. The resulting Michael adducts represent excellent building blocks for the synthesis of chiral indoles. The asymmetric Michael reaction using a modified Jorgensen-Hayashi organocatalyst in EtOH:brine solvent media is reported. This procedure afforded the corresponding Michael adducts in good yields and with excellent enantioselectivities. The resulting adducts were further used as chiral building blocks for the synthesis of indoles. Copyright
Feu, Karla Santos,Deobald, Anna Maria,Narayanaperumal, Senthil,Correa, Arlene G.,Weber Paixao, Marcio
p. 5917 - 5922
(2013/09/23)

Synthesis and evaluation of C8-substituted 4.5-spiro lactams as Glycogen Phosphorylase a inhibitors
An effective synthesis of 4.5-spiro lactams 28/29, has been completed in nine steps with an overall yield of 5.8%. The 4.5-spiro lactams were made from 2-allyl-Cbz-Pro-OMe 21, which was converted into the corresponding alcohol 22 via a hindered borane reaction with (2-methylbutyl)2borane. Subsequent Swern oxidation of 22 gave novel aldehyde 23. Aldehyde 23 was treated under Bucherer-Bergs reaction conditions to give hydantoin 26, which was opened to the corresponding amino acid 30 using di-tert-butyl dicarbonate and DMAP followed by hydrolysis. Treatment of amino acid 30 with acidic methanol gave 4.5-spiro lactams 28/29. Only 4.5-spiro lactam 29 displayed moderate activity against GPa with an IC50 of 241 μM.
Loughlin, Wendy A.,Schweiker, Stephanie S.,Jenkins, Ian D.,Henderson, Luke C.
supporting information
p. 1576 - 1582
(2013/03/29)

New route for the synthesis of chiral hydrazine SADP
A convenient route for the synthesis of (S)-1-amino-2-(1-methoxy-1- methylethyl)pyrrolidine (SADP) was established. The route involved three key steps viz. the Grignard addition to the N-Boc-proline ester (1), nitrosation to the aminoalcohol hydrochloride (3) and O-methylation to the alcohol group of N-nitrosopyrrolidine (4). (S)-1,1-dimethyl-tetrahydropyrrolo[1,2-c]oxazol-3-one (6) was also obtained via the reaction of (S)-1-Boc-2-(1-hydroxy-1-methylethyl) pyrrolidine (2) with sodium hydride.
Jia, Tao
experimental part
p. 325 - 328
(2012/09/22)

Practical one-pot double functionalizations of proline
Solubilization of proline as the triethylammonium salt allows N-protection (as the Boc, Cbz or Moc derivative) and subsequent esterification or amidation of the carboxy terminus to be performed in an efficient one-pot fashion. Based on this concept, highly practical protocols were developed to prepare a series of proline derivatives (including Pro-Ser dipetides, Weinreb amides and N-protected proline esters), which are important intermediates, for instance, for the synthesis of proline-derived peptides, chiral reagents and catalysts for asymmetric synthesis. Georg Thieme Verlag Stuttgart - New York.
Huy, Peter,Schmalz, Hans-Guenther
scheme or table
p. 954 - 960
(2011/05/07)

Highly enantioselective henry reactions in water catalyzed by a copper tertiary amine complex and applied in the synthesis of (S)-N-trans-feruloyl octopamine
It's in the water! A new copper tertiary amine complex was prepared and applied in asymmetric Henry reactions in water and in the short synthesis of (S)-N-trans-feruloyl octopamine. This catalytic system provided an approach to the enantioselective Henry reaction of aldehydes with hydroxyl substituents (see graphic).
Lai, Guoyin,Guo, Fengfeng,Zheng, Yueqin,Fang, Yang,Song, Haigang,Xu, Kun,Wang, Sujing,Zha, Zhenggen,Wang, Zhiyong
p. 1114 - 1117
(2011/03/21)

Enantioselective formal total synthesis of the Dendrobatidae frog toxin, (+)-pumiliotoxin B, via O-directed alkyne free radical hydrostannation
Herein we describe our application of the O-directed free radical hydrostannation of disubstituted alkylacetylenes (with Ph3SnH and Et3B) to the (+)-pumiliotoxin B total synthesis problem. Specifically, we report on the use of this method in the synthesis of the Overman alkyne 8, and thereby demonstrate the great utility of this process in a complex natural product total synthesis setting for the very first time. We also report here on a new, stereocontrolled, and highly practical enantioselective pathway to Overman's pyrrolidine epoxide partner 9 for 8, which overcomes the previous requirement for use of preparative HPLC to separate the 1:1 mixture of diastereomeric epoxides that was obtained in the original synthesis of 9.
Manaviazar, Soraya,Hale, Karl J.,LeFranc, Amandine
scheme or table
p. 2080 - 2084
(2011/05/09)

Enantioselective synthesis of functionalized 3,4-dihydropyran derivatives organocatalyzed by a novel fluorinated-diphenylprolinolether
A novel fluorinated diarylprolinol silyl ether catalyst have been designed and it successfully applicated in?the first asymmetric Michael addition-cyclization reaction between 1,3-dicarbonyl compounds with α,β-unsaturated aldehydes at room temperature. The products were isolated in good yields with high diastereoselectivities and enantioselectivities.
Yu, Chuanming,Zheng, Fei,Ye, Haiwei,Zhong, Weihui
scheme or table
p. 10016 - 10021
(2010/03/01)

Constrained peptidomimetics reveal detailed geometric requirements of covalent prolyl oligopeptidase inhibitors
Prolyl oligopeptidases cleave peptides on the carboxy side of internal proline residues and their inhibition has potential in the treatment of human brain disorders. Using our docking program FITTED, we have designed a series of constrained covalent inhibitors, built from a series of bicyclic scaffolds, to study the optimal shape required for these small molecules. These structures bear nitrile functional groups that we predicted to covalently bind to the catalytic serine of the enzyme. Synthesis and biological assays using human brain-derived astrocytic cells and endothelial cells and human fibroblasts revealed that these compounds act as selective inhibitors of prolyl oligopeptidase activity compared to prolyl-dipeptidyl-aminopeptidase activity, are able to penetrate the cells and inhibit intracellular activities in intact living cells. This integrated computational and experimental study shed light on the binding mode of inhibitors in the enzyme active site and will guide the design of future drug-like molecules.
Lawandi, Janice,Toumieux, Sylvestre,Seyer, Valentine,Campbell, Philip,Thielges, Sabine,Juillerat-Jeanneret, Lucienne,Moitessier, Nicolas
experimental part
p. 6672 - 6684
(2010/04/28)

(3R,7aS)-3-(Trichloromethyl)Tetrahydropyrrolo[1,2-C]oxazol-1(3h)-One: An Air and moisture stable reagent for the synthesis of optically active α-branched prolines
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Artman Iii, Gerald D.,Rafferty, Ryan J.,Williams, Robert M.,Aaron, Gregory L.,Davis, Matthew M.,Brummond, Kay M.
body text
p. 262 - 273
(2011/03/23)

Functional analysis of an aspartate-based epoxidation catalyst with amide-to-alkene peptidomimetic catalyst analogues
Subtle exchange: Replacement of an amide function with alkene or fluoroalkene groups provides a new class of epoxidation catalysts (see scheme). The structure-dependent catalytic behavior of these isosteric peptides provides mechanistic insights in their mode of action. (Chemical Equation Presented).
Jakobsche, Charles E.,Peris, Gorka,Miller, Scott J.
supporting information; experimental part
p. 6707 - 6711
(2009/03/12)

Catalytic asymmetric hydrogenation of 2,3,5-trisubstituted pyrroles
Catalytic asymmetric hydrogenation of N-Boc-protected pyrroles proceeded with high enantioselectivity by using a ruthenium catalyst modified with a trans-chelating chiral bisphosphine PhTRAP. The ruthenium catalyst prepared from Ru(η3-methallyl
Kuwano, Ryoichi,Kashiwabara, Manabu,Ohsumi, Masato,Kusano, Hiroki
p. 808 - 809
(2008/09/20)

An efficient and chemoselective Br?nsted acidic ionic liquid-catalyzed N-Boc protection of amines
The first report of a Br?nsted acidic ionic liquid, 1-methylimidazolium tetrafluoroborate [(HMIm)BF4], catalyzed efficient and chemoselective N-Boc protection of various amines using (Boc)2O is presented. Optically pure amino alcohols and amino acid esters were converted efficiently to their corresponding optically pure N-Boc derivatives. The reported method is mild, solvent-free and has the advantages of both homogeneous and heterogeneous catalysis with high product yields, selectivity and ease of product separation.
Sunitha, Sadula,Kanjilal, Sanjit,Reddy, P. Srinivasa,Prasad, Rachapudi B.N.
p. 2527 - 2532
(2008/09/19)

Attempts to mimic key bond-forming events associated with the proposed biogenesis of the pentacyclic lamellarins
The pyrrole-tethered veratroles 16 and 27 each engage in PIFA-induced oxidative cyclization reactions to give compounds 22 and 29, respectively, which incorporate a key tricyclic fragment associated with the title natural products. In contrast, the corresponding catechols 11 and 12 only produce polymeric materials on subjection to analogous reaction conditions. Efforts to study lactone ring formation by the oxidative cyclization of catechol 30 and veratrole 38 have been thwarted by an inability to prepare the former substrate and decomposition of the latter. The reported conversions 44 ? 45 and 46 ? 47 suggest that a C2-carboxy group attached to the pyrrole ring can ?direct' the oxidative cyclization of N-tethered aryl groups. The acquisition of compound 22 by the means described herein provides an adventitious and concise route to the racemic modification of the pyrrolo[2,1-a]isoquinoline alkaloid crispine A (52). CSIRO 2008.
Axford, Lorraine C.,Holden, Kate E.,Hasse, Katrin,Banwell, Martin G.,Steglich, Wolfgang,Wagler, Joerg,Willis, Anthony C.
p. 80 - 93
(2008/04/04)

Synthesis of GABAA receptor agonists and evaluation of their α-subunit selectivity and orientation in the GABA binding site
Drugs used to treat various disorders target GABAA receptors. To develop α subunit selective compounds, we synthesized 5-(4-piperidyl)-3-isoxazolol (4-PIOL) derivatives. The 3-isoxazolol moiety was substituted by 1,3,5-oxadiazol-2-one, 1,3,5-oxadiazol-2-thione, and substituted 1,2,4-triazol-3-ol heterocycles with modifications to the basic piperidine substituent as well as substituents without basic nitrogen. Compounds were screened by [3H]muscimol binding and in patch-clamp experiments with heterologously expressed GABAA αiβ 3γ2 receptors (i = 1-6). The effects of 5-aminomethyl-3H-[1,3,4]oxadiazol-2-one 5d were comparable to GABA for all α subunit isoforms. 5-piperidin-4-yl-3H-[1,3,4]oxadiazol-2-one 5a and 5-piperidin-4-yl-3H-[1,3,4]oxadiazol-2-thione 6a were weak agonists at α2-, α3-, and α5-containing receptors. When coapplied with GABA, they were antagonistic in α2-, α4-, and α6-containing receptors and potentiated α3-containing receptors. 6a protected GABA binding site cysteine-substitution mutants α1F64C and α1S68C from reacting with methanethiosulfonate-ethylsulfonate. 6a specifically covalently modified the α1R66C thiol, in the GABA binding site, through its oxadiazolethione sulfur. These results demonstrate the feasibility of synthesizing α subtype selective GABA mimetic drugs.
Jansen, Michaela,Rabe, Holger,Strehle, Axelle,Dieler, Sandra,Debus, Fabian,Dannhardt, Gerd,Akabas, Myles H.,Lüddens, Hartmut
supporting information; experimental part
p. 4430 - 4448
(2009/06/06)

S-6-METH0XY-2- (2- (3- (PYRIMID-2-YL) IS0XAZ0L-5-YL) PYRROLIDIN-1-YL) -4- (5-METHYL-IH-PYRAZOL-S-YLAMINO) PYRIMIDINE AND POLYMORPHIC FORMS THEREOF AS MODULATORS OF THE INSULIN-LIKE GROWTH
There is provided novel pyrimidine derivatives of formula (I) or pharmaceutically acceptable salsts thereof, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
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Page/Page column 38

(2008/12/04)

Spirobicyclic diamines. Part 3: Synthesis and metal complexation of proline-derived [4.4]-spirodiamines
The syntheses of racemic and homochiral [4.4]-spirolactams, starting from l-proline, in good yields are described. Reduction of the lactam carbonyl group of spirolactams, containing chiral substituents on the lactam nitrogen, with lithium aluminium hydride, gives?a series of homochiral [4.4]-spirodiamines. The crystal structure of one of these spirodiamines on complexation with zinc chloride was obtained. Interestingly it showed a hydrogen-bonded dimeric structure, where the monomers are diastereoisomeric diamines.
Kelleher, Fintan,Kelly, Sinead,McKee, Vickie
p. 9235 - 9242
(2008/02/10)

Modulators of 11-beta hydroxyl steroid dehydrogenase type 1, pharmaceutical compositions thereof, and methods of using the same
The present invention relates to inhibitors of 11-β hydroxyl steroid dehydrogenase type 1 and pharmaceutical compositions thereof. The compounds of the invention can be useful in the treatment of various diseases associated with expression or activity of
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Page/Page column 18

(2010/11/28)

Comparison of enantioselective reductions using bead and monolith 'disk' polymer formulations of CBS catalysts
Two polymer-supported versions of the Corey, Bakshi, and Shibata (CBS) catalyst were prepared and examined. Polymeric beads, with the auxiliary bound in pendant and crosslinked fashion, were prepared utilizing an improved procedure based upon earlier work. Optimization of a procedure for ketone reduction gives results that match those in solution. Attempted reuse gave mixed results. For comparison purposes, CBS functionalized monoliths were formed and tested but performed poorly.
Varela, Michael C.,Dixon, Seth M.,Price, Michael D.,Merit, Jeffrey E.,Berget, Patrick E.,Shiraki, Saori,Kurth, Mark J.,Schore, Neil E.
p. 3334 - 3339
(2007/10/03)

Spirobicyclic diamines 1: synthesis of proline-derived spirolactams via thermal intramolecular ester aminolysis
Proline-derived [4.4]-spirolactams have been synthesised in good yields by a reductive-amination reaction followed by thermal cyclisation of the resulting amine onto the proline ester group in refluxing toluene. The synthesis of the corresponding [4.5]-spirolactams by the same method gave much reduced yields.
Kelleher, Fintan,Kelly, Sinead
p. 3005 - 3008
(2007/10/03)