- Synthesis of 8-deoxypumiliotoxin 193H and 9-deoxyhomopumiliotoxin 207O
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The asymmetric synthesis of 8-deoxypumiliotoxin 193H and 9-deoxyhomopumiliotoxin 207O has been achieved, starting from both enantiomers of (+)- and (?)-10. Enantiomerically pure alcohols (+)- and (?)-10 were obtained by lipase-mediated kinetic resolution of racemic 10, which was prepared in 3 steps from new lactam-type building block (?)-8 in a highly stereoselective manner.
- Okada, Takuya,Yamamoto, Taiga,Kato, Daiki,Kawasaki, Masashi,Saporito, Ralph A.,Toyooka, Naoki
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- Easy approach to 3-benzylimino-2-pyrrolidinones from 3-chloro-4-chloromethyl-2-pyrrolidinones
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3-Benzylimino-2-pyrrolidinones can be prepared in good yield by heating 3-chloro-4-chloromethyl-2-pyrrolidinones, benzylamine and NaI in THF at 80°C. An endo-dehydrohalogenation followed by a SN2' substitution on the intermediate allyl chloride
- Ghelfi, Franco,Ghirardini, Gianluca,Libertini, Emanuela,Forti, Luca,Pagnoni, Ugo M.
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Read Online
- Discovery and Early Clinical Development of LY3202626, a Low-Dose, CNS-Penetrant BACE Inhibitor
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The beta-site APP cleaving enzyme 1, known as BACE1, has been a widely pursued Alzheimer's disease drug target owing to its critical role in the production of amyloid-beta. We have previously reported the clinical development of LY2811376 and LY2886721. L
- McKinzie, David L.,Winneroski, Leonard L.,Green, Steven J.,Hembre, Erik J.,Erickson, Jon A.,Willis, Brian A.,Monk, Scott A.,Aluise, Christopher D.,Baker, Thomas K.,Lopez, Jose E.,Hendle, J?rg,Beck, James P.,Brier, Richard A.,Boggs, Leonard N.,Borders, Anthony R.,Cocke, Patrick J.,Garcia-Losada, Pablo,Lowe, Stephen L.,Mathes, Brian M.,May, Patrick C.,Porter, Warren J.,Stout, Stephanie L.,Timm, David E.,Watson, Brian M.,Yang, Zhixiang,Mergott, Dustin J.
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p. 8076 - 8100
(2021/06/28)
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- MACROCYCLIC COMPOUNDS AND THEIR USE IN THE TREATMENT OF DISEASE
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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 65
(2020/07/14)
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- Evaluating the Viability of Successive Ring-Expansions Based on Amino Acid and Hydroxyacid Side-Chain Insertion
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The outcome of ring-expansion reactions based on amino/hydroxyacid side-chain insertion is strongly dependent on ring size. This manuscript, which builds upon our previous work on Successive Ring Expansion (SuRE) methods, details efforts to better define the scope and limitations of these reactions on lactam and β-ketoester ring systems with respect to ring size and additional functionality. The synthetic results provide clear guidelines as to which substrate classes are more likely to be successful and are supported by computational results, using a density functional theory (DFT) approach. Calculating the relative Gibbs free energies of the three isomeric species that are formed reversibly during ring expansion enables the viability of new synthetic reactions to be correctly predicted in most cases. The new synthetic and computational results are expected to support the design of new lactam- and β-ketoester-based ring-expansion reactions.
- Lawer, Aggie,Epton, Ryan G.,Stephens, Thomas C.,Palate, Kleopas Y.,Lodi, Mahendar,Marotte, Emilie,Lamb, Katie J.,Sangha, Jade K.,Lynam, Jason M.,Unsworth, William P.
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supporting information
p. 12674 - 12683
(2020/09/17)
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- Reactions of Hexadehydro-Diels-Alder (HDDA)-Derived Benzynes with Thioamides: Synthesis of Dihydrobenzothiazino-Heterocyclics
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Reaction of thioamides (e.g., II) with benzynes generated by the hexadehydro-Diels-Alder (HDDA) cycloisomerization (e.g., I) produces dihydrobenzothiazines (e.g., III). It is postulated that the reaction proceeds via benzothietene (cf. IV) and o-thiolatoa
- Palani, Vignesh,Chen, Junhua,Hoye, Thomas R.
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supporting information
p. 6312 - 6315
(2016/12/23)
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- BACE INHIBITORS
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The present invention provides compounds of Formula I useful as BACE inhibitors in the treatment of e.g. Alzheimer's disease : wherein A is selected from the group consisting of; of; R1 is H or F; R2 is H, -OCH3, C1-C3 alkyl,; R3 is H, -CH3, or -OCH3; and R4 is H or F; or a pharmaceutically acceptable salt thereof.
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Page/Page column 20-21
(2014/05/24)
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- A versatile polypeptoid platform based on N-allyl glycine
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N-Allyl glycine N-carboxyanhydride (NCA) was synthesized and polymerized by ring opening polymerization under homo- or heterophase conditions to afford well-defined polypeptoids (MW = 1.5-10.5 kg mol-1, PDI = 1.1-1.4). Poly(N-allyl glycine) demonstrated stimuli-responsive behaviour in water and was readily modified via thiol-ene photochemistry under experimentally benign conditions. This journal is
- Robinson, Joshua W.,Schlaad, Helmut
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supporting information; experimental part
p. 7835 - 7837
(2012/08/29)
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- Efficient and stereodivergent synthesis of deoxyimino sugars
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Both cis- and trans-2-substituted-1,2,3,6-tetrahydro-pyridin-3-ols have been prepared via an aldol condensation-ring-closing metathesis sequence. A stereodivergent synthesis of optionally functionalized deoxyimino sugars was achieved via asymmetric dihydroxylation or epoxidation/nucleophilic substitution of these tetrahydropyridines.
- Hong, Bor-Cherng,Chen, Zhong-Yi,Nagarajan, Arumugam,Kottani, Rudresha,Chavan, Vishal,Chen, Wei-Hung,Jiang, Yea-Fen,Zhang, Shuo-Cang,Liao, Ju-Hsiou,Sarshar, Sepehr
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p. 2457 - 2468
(2007/10/03)
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- Novel lincomycin derivatives possessing antimicrobial activity
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Novel lincomycin derivatives are disclosed. These lincomycin derivatives exhibit antibacterial activity. The compounds of the subject invention may exhibit potent activities against bacteria, including gram positive organisms, and may be useful antimicrobial agents. Methods of synthesis and of use of the compounds are also disclosed.
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- Novel lincomycin derivatives possessing antibacterial activity
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Novel lincomycin derivatives are disclosed. These lincomycin derivatives exhibit antibacterial activity. The compounds of the subject invention may exhibit potent activities against bacteria, including Gram positive organisms, and may be useful antimicrobial agents. Methods of synthesis and of use of the compounds are also disclosed.
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- A general approach to dehydro-Freidinger lactams: Ex-chiral pool synthesis and spectroscopic evaluation as potential reverse turn inducers
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Starting from natural α-amino acids, a practical synthesis of the dehydro-Freidinger lactams 9a-h based on the ring-closing olefin metathesis reaction was investigated. The presented examples comprise 6-, 7-, 8-, 9-, and 10-membered cyclic dipeptide mimics. Structural variations were demonstrated. We approached the metathesis precursors 8a-h employing an N-alkylation/peptide-coupling strategy. Subsequent ring closure was promoted by the ruthenium-based catalyst 10a or 10b. The resulting tetraresidue 11d was shown to undergo intramolecular hydrogen bonding based on NMR and FT-IR studies. Thus, the development of dehydro-Freidinger lactams as potential reverse turn inducers stabilizing an intramolecular NHi+3...COi hydrogen-bond was demonstrated.
- Hoffmann, Tobias,Waibel, Reiner,Gmeiner, Peter
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- Short and efficient synthesis of Homo-Freidinger lactams: An olefin metathesis approach towards conformationally restricted β-amino acid analogues
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Peptide coupling of the N-allyl or N-homoallyl α-amino acid esters 6a-d with enantiomerically pure β-C-allylglycine gave access to the dienes 7a-d which were subjected to an olefin metathesis reaction. Thus, the novel lactam bridged peptide mimics 8a-d we
- Hoffmann, Tobias,Gmeiner, Peter
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p. 1014 - 1016
(2007/10/03)
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- Synthesis of cyclic dipeptides by ring-closing metathesis
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Several cyclic dipeptides (4a-g and 9a-c) have been synthesized by 'amide-to-amide' cyclization of 2a-g and 8a-c, respectively, by means of ring-closing metathesis employing the Grubbs ruthenium catalyst. The influence of additives as well as the length of the amide substituent were studied. Best yields were obtained by cyclization in solution with either lithium fluoroacetate or α,α-dichlorotoluene as an additive.
- Reichwein, John F.,Liskamp, Rob M. J.
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p. 2335 - 2344
(2007/10/03)
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- Pd-catalyzed asymmetric allylic alkylation of 3-acetoxy-N-(tert- butyloxycarbonyl)-1,2,3,6-tetrahydropyridine - Preparation of key intermediates for natural product synthesis
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A convenient synthesis of racemic tetrahydropyridine 1 was developed. Pd-catalyzed allylic alkylation of 1 with malonate and dimethylacetoxymalonate as nucleophiles with the phosphanylcarboxylic acid L1 and the dihydrooxazol L2 as ligands, were carried out and gave enantiomeric excesses of up to 98%. Absolute configurations were determined for all compounds described. From the alkylation products (+)- and (-)-2a, and (+)- and (-)-2b a variety of versatile, nonracemic chiral intermediates were prepared.
- Schleich, Simone,Helmchen, Guenter
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p. 2515 - 2521
(2007/10/03)
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- Synthesis and reactions of 9,10-diazatetracyclo-[6.3.0.0.4,110.5.9]undecanes
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The tandem 1,3-dipolar cycloaddition between sydnones and 1,5-cyclooctadiene provides 9,10-diazatetracyclo[6.3.0.0.4,110.5,9]undecanes (the Weintraub reaction) in modest to good yields.
- Gribble, Gordon W.,Hirth, Bradford H.
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p. 719 - 726
(2007/10/03)
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- Sequential 1,3-dipolar cycloaddition-palladium catalysed cyclisation. A powerful new tactical combination
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A new flexible tactical combination of a 1,3-dipolar cycloaddition of an in situ generated azomethine ylide followed by a palladium catalysed cyclisation is described. The two reactions can be carried out as a 1 pot procedure if desired. Four new stereoce
- Grigg, Ronald,Coulter, Thomas
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p. 1359 - 1362
(2007/10/02)
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- Formation of Pyridazinooxazin-8(7H)-ones by Intramolecular Cycloaddition of Azoalkenes
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The hydrazides (3) and (4) of 2-allyloxyalkanoic acids (1) and prop-2-ynyloxyacetic acid have been prepared.These hydrazides have then been converted into the hydrazones (6) and (7), respectively, by reaction with phenacyl chloride.The azoalkenes have been generated from the hydrazones by reaction with sodium carbonate.The products isolated were the pyridazino-oxazinones (8) and (9) , formed by spontaneous intramolecular cycloaddition reactions of the azoalkenes.The hydrazones (6b) and (6c) with asymmetric carbon centres adjacent to the carbonyl groups each gave mixtures of diastereoisomeric oxazines but there was considerable selectivity (6:1) in each case.This is ascribed to steric effects in the transition states.An analogous series of conversions has been carried out with the hydrazones derived from the hydrazides (3) and (4) and ethyl bromopyruvate.N-Acetyl-N-allylglycine hydrazide (11) has also been prepared.The hydrazones (13) formed from this hydrazide and phenacyl chloride was converted by reaction with sodium carbonate into an azoalkene which cyclised to give the pyrazinopyridazin-8-one (14a).
- Gilchrist, Thomas L.,Wasson, Robert C.,King, Frank D.,Wootton, Gordon
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p. 2517 - 2522
(2007/10/02)
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- Pyrazolo[3,4-b]pyrrolo[3,4-e]pyridine-5(1H)-one and 1-H-pyrazolo[3,4-b][1,6]naphthyridine-5(6H)-one derivations, useful as anti-anxiety agents
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Novel pyrazolo[3,4-b]pyridine lactams which are useful as anxiolytics are disclosed including methods of preparation, pharmaceutical compositions containing them and intermediates used in their preparation.
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- N-Heterocyclic-9-xanthenylamines
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The compounds are N-piperidinyl and pyrrolidinyl-9-xanthenylamines which are inhibitors of gastric acid secretion.
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