cas 51693-17-5, (S)-(+)-5-(Hydroxymethyl)-2-pyrrolidinone p-toluenesulfonate

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Synthesis of N-aminomethylpyrrolidin-2-ones
Pyrrolidin-2-ones react with formaldehyde and chlorotrimethylsilane to give 1-chloromethylpyrrolidin-2-ones which upon subsequent reaction with primary and secondary amines give 1-aminomethylpyrrolidin-2-ones in good yield.
Chen, Ping,Suh, Dong-Jin,Smith, Michael B.
p. 1317 - 1322
(1995)
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(S)-4-Amino-5-phenoxypentanoate designed as a potential selective agonist of the bacterial transcription factor GabR
Addressing molecular recognition in the context of evolution requires pursuing new molecular targets to enable the development of agonists or antagonists with new mechanisms of action. Disruption of transcriptional regulation through targeting transcription factors that regulate the expression of key enzymes in bacterial metabolism may provide a promising method for controlling the bacterial metabolic pathways. To this end, we have selectively targeted a bacterial transcription regulator through the design and synthesis of a series of γ-aminobutyric acid (GABA) derivatives, including (S)-4-amino-5-phenoxypentanoate (4-phenoxymethyl-GABA), which are based on docking insights gained from a previously-solved crystal structure of GabR from Bacillus subtilis. This target was selected because GabR strictly controls GABA metabolism by regulating the transcription of the gabT/D operon. These GabR transcription modulators are selective for the bacterial transcription factor GabR and are unable to bind to structural homologs of GabR due to distinct steric constraints. We have obtained a crystal structure of 4-phenoxymethyl-GABA bound as an external aldimine with PLP in the effector binding site of GabR, which suggests that this compound is capable of binding and reacting in the same manner as the native effector ligand. Inhibition assays demonstrate high selectivity of 4-phenoxymethyl-GABA for bacterial GabR versus several selected eukaryotic enzymes. Single-molecule fluorescence resonance energy transfer (smFRET) experiments reveal a ligand-induced DNA distortion that is very similar to that of the native effector GABA, suggesting that the compound functions as a potential selective agonist of GabR.
Catlin, Daniel S.,Reidl, Cory T.,Trzupek, Thomas R.,Silverman, Richard B.,Cannon, Brian L.,Becker, Daniel P.,Liu, Dali
p. 1816 - 1828
(2020)
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Photoredox-Catalyzed Synthesis of α-Amino Acid Amides by Imine Carbamoylation
An operationally simple protocol for the photocatalytic carbamoylation of imines is reported. Easily available, bench-stable 4-amido Hantzsch ester derivatives serve as precursors to carbamoyl radicals that undergo rapid addition to N-aryl imines. The reaction proceeds under blue light irradiation in the presence of the photocatalyst 3DPAFIPN and Br?nsted/Lewis acid additives. Mechanistic studies indicated a photoredox mechanism that involves carbamoyl radicals.
Cardinale, Luana,Jacobi Von Wangelin, Axel,Konev, Mikhail O.,Schmotz, Mattis-Ole W. S.
supporting information

(2022/01/20)

NOVEL FUNCTIONALIZED LACTAMS AS MODULATORS OF THE 5-HYDROXYTRYPTAMINE RECEPTOR 7 AND THEIR METHOD OF USE
Described herein are new, selective modulators of the 5 -HT7 receptor. These selective compounds can be useful for the treatment of CNS and non-CNS indications. Compounds described herein can be selective in targeting 5-HT7 receptors
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Paragraph 000723-000724

(2021/05/21)

A class of histone acetylase p300 inhibitors, and application thereof
The invention discloses a class of histone acetylase p300 inhibitors, and application thereof, and belongs to the technical field of medicinal chemistry. The invention discloses a compound representedby a formula (I), or a stereochemical isomer, a solvate or a pharmaceutically acceptable salt thereof. According to the invention, the compound can effectively inhibit the activity of histone acetylase p300 and can effectively inhibit the proliferation activity of various tumor cells; the compound is combined with a CDK4/6 inhibitor to play a synergistic role in inhibiting proliferation of tumorcells; and the compound has good application prospects in preparation of histone acetylase inhibitors, preparation of drugs for preventing and/or treating cancers, metabolic diseases, neurological diseases or inflammations, and combination of drugs.
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Paragraph 1087-1091

(2020/06/17)

AMIDE DERIVATIVE INHIBITOR AND PREPARATION METHOD AND APPLICATION THEREOF
An amide derivative inhibitor and a preparation method and an application thereof. Specifically relating to the compound shown in general formula (I), a preparation method for same, a pharmaceutical composition comprising said compound, and an application of same as an ASK inhibitor for the treatment of neurodegenerative disease, cardiovascular disease, inflammation, autoimmune and metabolic disease, each of the substituents in the general formula (I) being as defined in the description.
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Paragraph 0254-0255

(2020/01/22)

IRAK DEGRADERS AND USES THEREOF
The present invention provides compounds, compositions thereof, and methods of using the same. The compounds include an IRAK binding moiety capable of binding to IRAK4 and a degradation inducing moiety (DIM). The DIM could be DTM a ligase binding moiety (LBM) or lysine mimetic. The compounds could be useful as IRAK protein kinase inhibitors and applied to IRAK mediated disorders.
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Paragraph 00920; 003256-003258

(2021/01/23)

MACROCYCLIC COMPOUNDS AND THEIR USE IN THE TREATMENT OF DISEASE
The invention relates to heterocyclic compounds of the formula (I), in which all of the variables are as defined in the specification; capable of modulating the activity of CFTR. The invention further provides a method for manufacturing compounds of the invention, and its therapeutic uses. The invention further provides methods to their preparation, to their medical use, in particular to their use in the treatment and management of diseases or disorders including Cystic fibrosis and related disorders.
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Page/Page column 71; 72

(2020/07/14)

Synthesis of optically active (R)- And (S)-β-arginine from pyroglutamic acid
– The first synthesis of optically active β-arginine was achieved starting from commercially available pyroglutamic acid. The new synthetic protocol is characterized by the use of nitrile as a carboxylic acid surrogate which could be transformed to the co
Yasuno, Yoko,Sawai, Akira,Sekihara, Ai,Shinada, Tetsuro
p. 165 - 176
(2020/02/04)

NOVEL FUNCTIONALIZED LACTAMS AS MODULATORS OF THE 5-HYDROXYTRYPTAMINE RECEPTOR 7 AND THEIR METHOD OF USE
Pharmaceutical compositions of the invention comprise functionalized lactam derivatives of formula (I) having a disease-modifying action in the treatment of diseases associated with dysregulation of 5- hydroxytryptamine receptor 7 activity. A is selected
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Paragraph 01130; 01131

(2019/11/28)

BETA-LACTAMASE INHIBITOR COMPOUNDS
The present invention is directed to compounds which are beta-lactamase inhibitors. The compounds and their pharmaceutically acceptable salts are useful in combination with beta- lactam antibiotics, for the treatment of bacterial infections, including infections caused by drug resistant organisms, including multi-drug resistant organisms. The present invention includes compounds according to Formula (I): or a pharmaceutically acceptable salt thereof, wherein the values of R1, R2, R3, R4, R5 and R6 are described herein.
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Page/Page column 167

(2018/04/13)

5-HT7 Receptor Antagonists with an Unprecedented Selectivity Profile
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Ates, Ali,Burssens, Pierre,Lorthioir, Olivier,Lo Brutto, Patrick,Dehon, Gwenael,Keyaerts, Jean,Coloretti, Francis,Lallemand, Bénédicte,Verbois, Valérie,Gillard, Michel,Vermeiren, Céline
p. 795 - 802
(2018/04/02)

A 5 - biphenyl -4 - amino -2 - methyl valeric acid synthesis of intermediates method
The invention provides a synthesis method of a new compound (3) disclosed in the specification and a synthesis method for preparing a 5-biphenyl-4-amino-2-methylvaleric acid intermediate from the compound (3). The method has excellent selectivity, and generates few diastereoisomers in the reaction process. The generated diastereoisomers can be removed just by simple recrystallization. Thus, the method is suitable for industrial production.
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Paragraph 0068-0071

(2018/10/19)

HETEROCYCLIC COMPOUNDS FOR THE TREATMENT OF DISEASE
Described herein are heterocyclic compounds, compositions, and methods for their use for the treatment of disease.
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Paragraph 00215

(2017/06/01)

MUSCARINIC AGONISTS
This invention relates to compounds that are agonists of the muscarinic M4 receptor and/or M4 receptor and which are useful in the treatment of muscarinic M1/M4 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds include those according to formula 1a or a salt thereof, wherein n, p, Q, R1, R2, R3, R9 and R4 are as defined herein.
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Page/Page column 47; 48

(2017/02/28)

Discovery of Indolinone-Based Multikinase Inhibitors as Potential Therapeutics for Idiopathic Pulmonary Fibrosis
Idiopathic pulmonary fibrosis (IPF) is a serious and deadly disease for which treatment options are limited. The recent approval of antifibrosis agent nintedanib represents one of the first therapeutic approaches for the treatment of IPF. Here, we report novel indolinone-based multikinase inhibitors that target angiogenesis and fibrosis pathways and may serve as potential therapeutics for IPF. KBP-7018 is a novel, tyrosine kinase-selective inhibitor with potent effects on three fibrotic kinases (c-KIT, PDGFR, and RET). The pharmacokinetics (PK) properties of KBP-7018 were favorable in mice, rats, and dogs. In a bleomycin (BLM)-induced mouse pulmonary fibrosis model, 10, 30, and 100 mg/kg daily doses (q.d.) of KBP-7018 improved the 28-day survival rate in a dose-dependent manner. The improved efficacy of KBP-7018 compared to nintedanib provided a certain level of chemical validation for the involvement of PDGFR, c-KIT, and RET in IPF. Thus, KBP-7018 represents a novel multikinase inhibitor with differentiated activity, highly enhanced selectivity, and acceptable PK profiles that will enter phase I clinical trials.
Huang, Zhenhua,Li, Heran,Zhang, Qian,Lu, Fangzheng,Hong, Mei,Zhang, Zhigang,Guo, Xiaocui,Zhu, Yuanju,Li, Sanming,Liu, Hongzhuo
supporting information
p. 1142 - 1147
(2017/11/15)

As tyrosine kinase inhibitors substituted indolinone derivatives
The invention belongs to the technical field of a medicine, and particularly relates to a substituted indole ketone derivative as a tyrosine kinase inhibitor shown in a general formula (I), a pharmaceutically acceptable salt, a deuterated article or a stereoisomer thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, Rc, Rd, n, n1, n2, n3, n4, a ring A and a ring B are defined in the specification. The invention also relates to a preparation method of the compound, a drug preparation containing the compound, and application of the compound in preparation of a drug for preventing or treating a fibrosis disease and treating an excessive hyperplasia disease.
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Paragraph 0367-0369

(2016/10/24)

Synthesis of a series of ω-dimethylaminoalkyl substituted ethylenediamine ligands for use in enantioselective catalysis
The title compounds H2NCH((CH2)nNMe2)CH2NH2 L1-L4 (n = 1-4) are efficiently synthesized in enantiopure form. The commercial starting materials, l-asparagine, (S)-5-hydroxymethyl-2-pyrrolidinone, and (S)-6-(((benzyloxy)carbonyl)-amino)-2-((tert-butoxycarbonyl)amino)hexanoic acid, are elaborated in 6-9 standard steps to give L1 (18% overall), L2 (13%), L3 (36%) and L4 (38%) or the corresponding tris(hydrochloric acid) salts [H3NCH((CH2)nNHMe2)CH2NH3]3+ 3Cl-, which are preferable for long term storage. The sequences make use of isobutyl carbamate, Cbz, and Boc protecting groups and Hofmann type rearrangements; the dimethylamino groups are introduced at late stages, either via reductive dimethylations or nucleophilic displacements involving mesylates and HNMe2. L1-L4 chelate to [Co(en)2]3+ fragments to give octahedral complexes that catalyze numerous enantioselective reactions.
Ghosh, Subrata K.,Ganzmann, Carola,Gladysz, John A.
p. 1273 - 1280
(2015/11/09)

BICYCLIC AZA COMPOUNDS AS MUSCARINIC M1 RECEPTOR AGONISTS.
This invention relates to compounds that are agonists of the muscarinic M1 receptor and/or M4 receptor and which are useful in the treatment of muscarinic M1/M4 receptor mediated diseases. Also provided are pharmaceutical compositions containing the compounds and the therapeutic uses of the compounds. Compounds include those according to formula 1, or a salt thereof, wherein Q, R1 , R2, R3 and R4 are as defined herein.
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Page/Page column 103

(2015/09/22)

TRANSITION METAL COMPLEXES FOR ENANTIOSELECTIVE CATALYSIS OF CARBON-CARBON, CARBON-HETEROATOM, AND CARBON-HYDROGEN BOND FORMING REACTIONS
In some embodiments, the present disclosure pertains to a compound, comprising a transition metal complex having the formula Φ-[Μ (x,y)-L1 (w,v)-L2 (t,u)-L3]p+An-mZ-p_m. In an embodiment of the present disclosure Φ may be A. In another embodiment Φ may be Δ. In some embodiments of the present disclosure, M is a transition metal. In a related embodiment, p is an integer corresponding to the oxidation state of M. In some embodiments of the present disclosure, each of x, y, w, v, t, and u independently comprise R. In other embodiments, each of x, y, w, v, t, and u independently comprise S. In an embodiment of the present disclosure, each of L1, L2, and L3 independently is a ligand comprising a substituted diamine. In some embodiments, An" comprises a lipophilic anion, where m is from 1 to 3, and where Z- comprises an optional second anion.
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Paragraph 00130; 00131

(2014/02/16)

First total synthesis of oteromycin utilizing one-pot four-step cascade reaction strategy
The first total synthesis of oteromycin was investigated. Our previously reported convergent strategy for the synthesis of α-acyl-γ-hydroxy- γ-lactams was first applied for the total synthesis, however, the final deprotection of the methoxyaminal moiety could not be achieved since an unexpected intramolecular Diels-Alder (IMDA) reaction occurred. Therefore, a novel one-pot four-step cascade reaction starting from α-selenolactam was investigated. The efficient synthetic strategy was successfully developed to afford the desired oteromycin, and its complete structure elucidation including the stereochemistry at C24 position was also accomplished.
Uchiro, Hiromi,Shionozaki, Nobuhiro,Tanaka, Ryo,Kitano, Hiroyuki,Iwamura, Naoki,Makino, Kimiko
p. 506 - 511
(2013/02/23)

Straightforward synthesis of non-natural l-chalcogen and l-diselenide N-Boc-protected-γ-amino acid derivatives
The synthesis of new chiral seleno-, telluro-, and thio-N-Boc-γ-amino acids is described herein. These new compounds were prepared through a simple and short synthetic route, from the inexpensive and commercially-available amino acid l-glutamic acid. The products, with a highly modular character, were obtained in good to excellent yields, via hydrolysis of chalcogen pyroglutamic derivatives with overall retention of the l-glutamic acid stereochemistry. Also, an l-diselenide-N-Boc-γ-amino acid was prepared in good yield. This new synthetic route represents an efficient method for preparing new l-chalcogen- and l-diselenide-γ-amino acids with biological potential.
Kawasoko, Cristiane Y.,Foletto, Patricia,Rodrigues, Oscar E. D.,Dornelles, Luciano,Schwab, Ricardo S.,Braga, Antonio L.
p. 5173 - 5183
(2013/08/15)

Synthesis of bicyclic γ-lactam derivatives by intramolecular carbene insertion and aza-Wittig reaction
A comparative study of the various methodologies to construct bicyclic γ-lactams is reported. Thus RhII-catalyzed decomposition of 2-pyrrolidone and pyrrolidine derived diazomalonates were attempted to synthesize fused γ-lactams. Spectral evidences revealed the formation of diastereomeric alcohols instead of desired C-H or N-H insertion products, indicating significant conformational bias towards insertion process. On the other hand, the method involving the N-H insertion onto the lactam nitrogen of 2-pyrrolidone ring was successful. Intramolecular aza-Wittig reaction was also successfully explored to construct bicyclic γ-lactam scaffolds. All the bicyclic analogues showed weak antibacterial activity against S. aureus and E. coli.
Roy, Basab,Hatial, Ishita,Ghosh, Debaki,Addy, Partha Sarathi,Basak, Amit
p. 1841 - 1851
(2014/01/17)

NOVEL AMIDE DERIVATIVE AND USE THEREOF AS MEDICINE
Provided are a novel low-molecular-weight compound that suppresses production of induction type MMPs, particularly MMP-9, rather than production of hemostatic type MMP-2, as well as a prophylactic/therapeutic drug for autoimmune diseases or osteoarthritis. An amide derivative represented by the following formula (I) wherein each symbol is as defined in the specification, or a pharmacologically acceptable salt thereof.
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Paragraph 0795; 0796; 0797

(2013/03/26)

Asymmetric transfer hydrogenation of aromatic ketones using rhodium complexes of chiral N-heterocyclic carbenes derived from (S)-pyroglutamic acid
A new and flexible procedure for the preparation of chiral azolium salts derived from (S)-pyroglutamic acid has been developed. The efficiency of these ligands has been evaluated in the metal-catalyzed asymmetric transfer hydrogenation of aromatic ketones in isopropanol. Good enantioselectivities up to 90%ee were observed.
Aupoix, Audrey,Bournaud, Chloee,Vo-Thanh, Giang
scheme or table
p. 2772 - 2776
(2011/06/23)

5-Lipoxygenase-activating protein inhibitors. Part 2: 3-{5-((S)-1-Acetyl-2,3-dihydro-1H-indol-2-ylmethoxy)-3-tert-butylsulfanyl-1-[4-(5-methoxy-pyrimidin-2-yl)-benzyl]-1H-indol-2-yl}-2,2-dimethyl-propionic acid (AM679)-A potent FLAP inhibitor
A series of potent 5-lipoxygenase-activating protein (FLAP) inhibitors are herein described. SAR studies focused on the discovery of novel alicyclic moieties appended to an indole core to optimize potency, physical properties and off-target activities. Subsequent SAR on the N-benzyl substituent of the indole led to the discovery of compound 39 (AM679) which showed potent inhibition of leukotrienes in human blood and in a rodent bronchoalvelolar lavage (BAL) challenge model.
Stock, Nicholas,Baccei, Christopher,Bain, Gretchen,Broadhead, Alex,Chapman, Charles,Darlington, Janice,King, Christopher,Lee, Catherine,Li, Yiwei,Lorrain, Daniel S.,Prodanovich, Pat,Rong, Haojing,Santini, Angelina,Zunic, Jasmine,Evans, Jilly F.,Hutchinson, John H.,Prasit, Peppi
scheme or table
p. 213 - 217
(2010/04/24)

Design of HIV-1 protease inhibitors with pyrrolidinones and oxazolidinones as novel P1′-ligands to enhance backbone-binding interactions with protease: Synthesis, biological evaluation, and protein-ligand X-ray studies
Structure-based design, synthesis, and biological evaluation of a series of novel HIV-1 protease inhibitors are described. In an effort to enhance interactions with protease backbone atoms, we have incorporated stereochemically defined methyl-2-pyrrolidinone and methyl oxazolidinone as the P1′-ligands. These ligands are designed to interact with Gly-27′ carbonyl and Arg-8 side chain in the S1′-subsite of the HIV protease. We have investigated the potential of these ligands in combination with our previously developed bis-tetrahydrofuran (bis-THF) and cyclopentanyltetrahydrofuran (Cp-THF) as the P2-ligands. Inhibitor 19b with a (R)-aminomethyl-2-pyrrolidinone and a Cp-THF was shown to be the most potent compound. This inhibitor maintained near full potency against multi-PI-resistant clinical HIV-1 variants. A high resolution protein-ligand X-ray crystal structure of 19b-bound HIV-1 protease revealed that the P1′-pyrrolidinone heterocycle and the P2-Cp-ligand are involved in several critical interactions with the backbone atoms in the S1′ and S2 subsites of HIV-1 protease.
Ghosh, Arun K.,Leshchenko-Yashchuk, Sofiya,Anderson, David D.,Baldridge, Abigail,Noetzel, Marcus,Miller, Heather B.,Tie, Yunfeng,Wang, Yuan-Fang,Koh, Yasuhiro,Weber, Irene T.,Mitsuya, Hiroaki
experimental part
p. 3902 - 3914
(2010/01/06)

Selenium-promoted synthesis of enantiopure octahydroindolizines, hexahydro-1H-pyrrolizines and hexahydro-3H-pyrrolizin-3-ones
Enantiomerically pure disubstituted pyrrolidines, recently synthesized from commercially available enantiomerically pure β-aminoalcohol, were used as starting materials to synthesize enantiomerically pure hexahydro-1H-pyrrolizines and octahydroindolizine through a cyclization reaction promoted by N-(phenylseleno)phthalimide. Similarly, starting from enantiopure 5-(hydroxymethyl)pyrrolidin-2-ones, enantiopure hexahydro-3H-pyrrolizin-3-ones were obtained.
Tiecco, Marcello,Testaferri, Lorenzo,Bagnoli, Luana,Scarponi, Catalina
scheme or table
p. 2411 - 2416
(2009/04/06)

Total synthesis of (-)-martinellic acid
An enantioselective formal total synthesis of the pyrrolo[3,2-c]quinoline natural product martinellic acid has been achieved. The key steps involve a Pd-catalyzed aryl amidation reaction of a pyrroglutamate derivative, an intramolecular [3+2] azomethine ylide-alkene cycloaddition and a reductive ring opening reaction.
Badarinarayana, Vivek,Lovely, Carl J.
p. 2607 - 2610
(2007/10/03)

BIARYL SUBSTITUTED HETEROCYCLE INHIBITORS OF LTA4H FOR TREATING INFLAMMATION
The present invention relates to a chemical genus of biaryl substituted heterocycle inhibitors of LTA4H (leukotriene A4 hydrolase) useful for the treatment and prevention and prophylaxis of inflammatory diseases and disorders. The compounds have general formula Ψ: An example is
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Page/Page column 54

(2008/06/13)

An optimised synthetic approach to a chiral derivatising agent and the utilisation of a dimerisation reaction in the synthesis of a novel C2-symmetric diphosphine ligand
We report an optimised synthetic approach to the chiral derivatising agent (5R)-methyl-1-(chloromethyl)-2-pyrrolidinone. In addition, the observation of an unwanted dimerisation product is turned to our advantage by providing a method for the synthesis of a new class of C2-symmetric chiral diphosphine.
Williams, Glynn D.,Wade, Charles E.,Clarkson, Guy J.,Wills, Martin
p. 664 - 670
(2007/10/03)

Stereoselective conjugate addition of lactams to nitroalkenes and formal total synthesis of indolizidine 167B
Optically active 5-substituted pyrrolidin-2-ones underwent conjugate addition to nitroalkenes to give the corresponding adducts in a diastereoselective manner. The presence of 18-crown-6 was crucial to achieve good stereoselective addition. Addition of 6-substituted piperidin-2-ones also gave the corresponding adduct in a stereoselective manner. The adduct was readily converted into a bicyclic lactam through intramolecular nitroaldol reaction, and the formal synthesis of indolizidine 167B was achieved.
Kamimura, Akio,Nagata, Yoshiaki,Kadowaki, Ayako,Uchida, Kosuke,Uno, Hidemitsu
p. 11856 - 11861
(2008/03/13)

Total synthesis of (+)-batzelladine A and (-)-batzelladine D via [4 + 2]-annulation of vinyl carbodiimides with N-alkyl imines
A diastereoselective [4 + 2]-annulation of vinyl carbodiimides with chiral N-alkyl imines has been developed to access the stereochemically rich polycyclic guanidine cores of the batzelladine alkaloids. Application of this strategy, together with additional key steps such as long-range directed hydrogenation and diastereoselective intramolecular iodo-amination, led to highly convergent total syntheses of (-)-batzelladine D and (+)-batzelladine A with excellent stereocontrol.
Arnold, Michael A.,Day, Kenneth A.,Duron, Sergio G.,Gin, David Y.
p. 13255 - 13260
(2008/03/11)

Copper(I) mediated cross-coupling of amino acid derived organozinc reagents with acid chlorides
This paper describes the development of a straightforward experimental protocol for copper-mediated cross-coupling of amino acid derived β-amido-alkylzinc iodides 1 and 3 with a range of acid chlorides. The present method uses CuCN·2LiCl as the copper source and for organozinc reagent 1 the methodology appears to be limited to reaction with more stable acid chlorides, providing the desired products in moderate yields. When applied to organozinc reagent 3, however, the protocol is more general and provides the products in good yields in all but one of the cases tested. The Royal Society of Chemistry 2006.
Hjelmgaard, Thomas,Tanner, David
p. 1796 - 1805
(2008/02/05)

Total synthesis of pinnamine and anatoxin-a via a common intermediate. A caveat on the anatoxin-a endgame
This paper describes the total synthesis of the naturally occurring alkaloids pinnamine (1) and anatoxin-a (2) from a common enantiomerically pure intermediate (7) easily available from pyroglutamic acid. The synthesis of enantiopure pinnamine proceeded in 10 steps and 4.8% overall yield, and the route was flexible enough to allow stereocontrolled access to a non-natural congener (5-epi-pinnamine) of the natural product. Intramolecular reaction of an N-acyl iminium ion was a key step in the synthesis of both pinnamine and anatoxin-a. However, in stark contrast to literature precedent, complete racemization was observed during the reaction of the N-acyliminium ion leading to the latter alkaloid.
Hjelmgaard, Thomas,Sotofte, Inger,Tanner, David
p. 5688 - 5697
(2007/10/03)

Remote stereocontrol in the Nazarov reaction: A new approach to the core of roseophilin
Three different procedures are compared to obtain properly substituted divinyl ketones in which one of the double bonds is embedded in a five-membered heterocyclic structure and therefore suitable to produce cyclopenta-fused pyrrole derivatives by the acid-catalyzed Nazarov reaction. These, on treatment with TFA, afforded 2,4-cis-disubstituted 2,3,4,5-tetrahydro-1H-cyclopenta[e] pyrrol-6-ones with high stereo-control. One of these Nazarov products was oxidized to the corresponding 4,5-dihydro-1H-cyclopenta[e]pyrrol-6-one derivative, thus obtaining an enantiopure key intermediate in the total synthesis of roseophilin.
Occhiato, Ernesto G.,Prandi, Cristina,Ferrali, Alessandro,Guarna, Antonio
p. 4542 - 4545
(2007/10/03)

Enantiospecific synthesis of an indolizidine alkaloid, (+)-ipalbidine
Enantiospecific total synthesis of an indolizidine alkaloid, ipalbidine, was achieved starting from (-)-pyroglutamic acid by employing an intramolecular McMurry coupling reaction with a low-valent titanium, as a key step.
Honda, Toshio,Namiki, Hidenori,Nagase, Hiromasa,Mizutani, Hirotake
p. 3035 - 3038
(2007/10/03)

PROTEASE INHIBITORS
This invention relates to 7-substituted 3,6-dioxo-octahydroprrolo[1,2- alpha ]azepine protease inhibitors of formula (1) as defined herein, particularly of cysteine and serine proteases.
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Page 22; 21

(2010/02/05)

Convergent asymmetric synthesis of indolizidines from (S)-5-(tosylmethyl)-2-pyrrolidinone: Synthesis of (-)-δ-coniceine
The enantiomerically pure (S)-5-(tosylmethyl)-2-pyrrolidinone 2, prepared from commercially available (S)-pyroglutaminol, is dialkylated at the nitrogen atom and the α-sulfonyl position using several dielectrophiles using sodium hydride as the base to diastereoselectively afford indolizidine derivatives 5 and the less common hexahydropyrrolo[1,2-a]azepin-3-one 6 in moderate to good yield. This domino process has been applied to the synthesis of (-)-δ-coniceine.
Costa, Ana,Najera, Carmen,Sansano, Jose M.
p. 2205 - 2211
(2007/10/03)

Approach to enantioselective conjugate addition of organocopper reagents to cycloalkenones by the aid of chiral lactam bearing phosphine group
The chiral lactam-phosphine ligand and copper salt mediated asymmetric conjugate addition reaction of butylmagnesium chloride and diethylzinc with cycloalkenones afforded the addition products in moderate selectivity. Among phosphines examined, 5-[(diphenylphosphiao)methyl]-3,3-dimethylpyrrolidin-2- one 5 gave rise to moderate enantioselectivity and high yield. (C) 2000 Elsevier Science Ltd.
Nakagawa, Yuichi,Matsumoto, Koichiro,Tomioka, Kiyoshi
p. 2857 - 2863
(2007/10/03)

The synthesis of (+)-preussin and related pyrrolidinols by diastereoselective Paterno-Buechi reactions of chiral 2-substituted 2,3-dihydropyrroles
The N-alkoxycarbonyl substituted 2,3-dihydropyrroles 3 and 8 are converted to 2-benzyl-3-pyrrolidinols by the Paterno - Buechi reaction followed by hydrogenolysis. Since the addition of the photoexcited benzaldehyde at the unsaturated heterocycle proceeds in a syn fashion, the benzyl group at C-2 and the hydroxy group at C-3 of the product are cis oriented. The simple and facial diastereoselectivities of the Paterno -Buechi reaction were studied more closely and the relative configuration of the products was elucidated. The thermodynamically less stable endo product is formed as a result of simple diastereo-selection. The face differentiation in 2-substituted 2,3-dihydropyrroles is presumably due to the nonplanarity of these heterocycles, which forces attack of the carbonyl group on the face with the existing substituent. All-cis-pyrrolidinols are consequently formed after hydrogenolysis. Following this route, a total synthesis of the pyrrolidinol alkaloid (+)-preussin (1) was conducted, which yielded the target compound in a total yield of 11% over nine steps starting from L-pyroglutaminol (11).
Bach, Thorsten,Brummerhop, Harm,Harms, Klaus
p. 3838 - 3848
(2007/10/03)

Unprecedented facial diastereoselectivity in the paterno - Buechi reaction of a chiral dihydropyrrole - a short total synthesis of (+)-preussin
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Bach, Thorsten,Brummerhop, Harm
p. 3400 - 3402
(2007/10/03)

The synthesis of di(hydroxyalkyl) substituted bicyclic guanidines
The synthesis of the enantiomerically pure bicyclic guanidines 3a and 3b is described.The convergent strategy is based on methodology developed by Schmidtchen.The therefore required amine components 6 and 9 obtained from methionine and L-glutamic acid, respectively.
Madder, A.,Muenster, I.,Rolle, U.,Clercq, P. J. De
p. 613 - 622
(2007/10/03)

Synthesis of a Chiral Di(hydroxyalkyl) Substituted Bicyclic Guanidine
Schmidtchen's methodology is used successfully for the synthesis of the chiral disubstituted bicyclic guanidinium salt 2.The two therefore required primary amine compounds 6 and 9 are obtained from L-methionine and L-glutamic acid, respectively.
Muenster, Ingo,Rolle, Ulrike,Madder, Annemieke,Clerq, Pierre J. De
p. 2673 - 2674
(2007/10/03)

5(R)-Methyl-1-(chloromethyl)-2-pyrrolidinone: A New Reagent for the Determination of Enantiomeric Composition of Alcohols
We have prepared a new chiral nonracemic reagent (5(R)-methyl-1-(chloromethyl)-2-pyrrolidinone) in enantiopure form that reacts with alcohols containing a stereogenic center to produce diastereomeric N-(alkoxymethyl)-2-pyrrolidinone derivatives.These derivatives exhibit large and easily observed diastereotopic signals in the proton NMR that allow direct determination of diastereomeric ratio (percent dr) for the product.
Smith, Michael B.,Dembofsky, Bruce T.,Son, Young Chan
p. 1719 - 1725
(2007/10/02)

Stereoselective Synthesis of (+/-)-Indolizidines 167B, 205A, and 207A. Enantioselective Synthesis of (-)-Indolizidine 209B
The first syntheses of the dendrobatid indolizidine alkaloids 167B (3), 205A (4), and 207A (5) are described using as a key step the highly stereoselective intramolecular nitrone cycloaddition of the (Z)-N-alkenylnitrone 10 to prepare the isoxazolidine 11.Mesylate-promoted cyclization of the alcohol 12, followed by reductive cleavage of the resulting mesylate salt, afforded the key axial hydroxymethyl compound 13, which was epimerized via the aldehyde to the equatorial alcohol, and was subsequently reduced to the required 8-methyl-substituted indolizidine.The feasibility of extending this strategy to the enantioselective synthesis of such alkaloids was demonstrated in the first synthesis of (-)-indolizidine 209B (6), whose precursor 10d was obtained from the (S)-glutamate-derived amine 40.
Holmes, Andrew B.,Smith, Adrian L.,Williams, Simon F.,Hughes, Leslie R.,Lidert, Zev,Swithenbank, Colin
p. 1393 - 1405
(2007/10/02)

Acyclic Nucleic Acid Analogues: Synthesis and Oligomerization of γ,4-Diamino-2-oxo-1(2H)-pyrimidinepentanoic Acid and δ,4-Diamino-2-oxo-1(2H)-pyrimidinehexanoic Acid
Alkylation of the tosylates of N-t-Boc-5-(hydroxymethyl)-2-pyrrolidinone and N-t-Boc-6-(hydroxymethyl)-2-piperidinone with the sodium salt of cytosine in dimethyl sulfoxide, followed by acylation of the base exocyclic amine and selective opening of the lactam ring by alkaline hydrolysis, gave the title compounds, respectively, in protected form.Oligomerization was achieved by activation of the carboxylic group as the p-nitrophenyl ester and coupling with the free amine of another subunit in dimethlformamide or dimethyl sulfoxide.A hexamer of the pentanoic acid system could be easily prepared by stepwise coupling of the monomeric units or by block synthesis via trimers.The hexanoic acid derived hexamer could only be prepared by stepwise elongation, mostly due to problems of solubility for this backbone.
Huang, Sung-Ben,Nelson, Jeffrey S.,Weller, Dwight D.
p. 6007 - 6018
(2007/10/02)

Stereoselective synthesis of (±)-indolizidines 167B, 205A, and 207A. Enantioselective synthesis of (-)-indolizidine 209B
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Smith,Williams,Holmes,Hughes,Lidert,Swithenbank
p. 8696 - 8698
(2007/10/02)

Process for preparing 5-vinyl-2-pyrrolidinone and intermediates therefor
4-Amino-5-hexenoic acid is prepared by: (a) reacting 5-oxo-2-pyrrolidine-acetonitrile with hydrogen and dimethylamine in the presence of a palladium catalyst to form N,N-dimethyl-2-[5'-oxo-2'-pyrrolidine]ethylamine; (b) oxidizing N,N-dimethyl-2-[5'-oxo-2'-pyrrolidine]-ethylamine to produce the corresponding N-oxide derivative; (c) pyrolysis of the N-oxide derivative to form 5-vinyl-2-pyrrolidinone; (d) optionally, separating N,N-dimethyl-2-[5'-oxo-2'-pyrrolidine]ethylamine by-product from the 5-vinyl-2-pyrrolidinone product; and (e) hydrolyzing 5-vinyl-2-pyrrolidinone to form 4-amino-5-hexenoic acid.
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(2008/06/13)