- Asymmetric synthesis of β-lactam via palladium-catalyzed enantioselective intramolecular c(sp3)-h amidation
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β-Lactams are important scaffolds in drug design and frequently used as reactive intermediates in organic synthesis. Catalytic reactions featuring intramolecular C-H amidation of alkyl carboxamide substrates could provide a straightforward disconnection strategy for β-lactam synthesis. Herein, we report a streamlined method for asymmetric synthesis of β-aryl β-lactams from propanoic acid and aryl iodides via Pd-catalyzed sequential C(sp3)-H functionalization. The lactam-forming reaction provides an example of PdII-catalyzed enantioselective intramolecular C(sp3)-H amidation reaction and proceeds up to 94% ee. The use of a 2-methoxy-5-chlorophenyl iodide oxidant is critical to control the competing reductive elimination pathways of the PdIV intermediate to achieve the desired chemoselectivity. Mechanistic studies suggest that both steric and electronic effects of the unconventional aryl iodide oxidant are responsible for controlling the competing C-N versus C-C reductive elimination pathways of the PdIV intermediate.
- Tong, Hua-Rong,Zheng, Wenrui,Lv, Xiaoyan,He, Gang,Liu, Peng,Chen, Gong
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Read Online
- PRMT5 INHIBITORS AND USES THEREOF
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Described herein are compounds of Formula (I)-(XIII), pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Compounds of the present invention are useful for inhibiting PRMT5 activity. Methods of using the compounds for treating PRMT5-mediated disorders are also described.
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Paragraph 00511
(2016/01/12)
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- The insulin secretory action of novel polycyclic guanidines: Discovery through open innovation phenotypic screening, and exploration of structure-activity relationships
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We report the discovery of the glucose-dependent insulin secretogogue activity of a novel class of polycyclic guanidines through phenotypic screening as part of the Lilly Open Innovation Drug Discovery platform. Three compounds from the University of California, Irvine, 1-3, having the 3- arylhexahydropyrrolo[1,2-c]pyrimidin-1-amine scaffold acted as insulin secretagogues under high, but not low, glucose conditions. Exploration of the structure-activity relationship around the scaffold demonstrated the key role of the guanidine moiety, as well as the importance of two lipophilic regions, and led to the identification of 9h, which stimulated insulin secretion in isolated rat pancreatic islets in a glucose-dependent manner.
- Shaghafi, Michael B.,Barrett, David G.,Willard, Francis S.,Overman, Larry E.
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supporting information
p. 1031 - 1036
(2014/03/21)
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- WNT PATHWAY ANTAGONISTS
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The present invention relates to known and novel compounds of formula (I) as herein described and pharmaceutical compositions thereof. The compounds of formula (I) have inhibitory effect on the Wnt pathway and are therefore useful in the preparation of a medicament, in particular for the treatment of cancer.
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Page/Page column 53-54
(2011/04/26)
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- Basic techniques of working on a solid phase: From ABC of the peptide synthesis to libraries of non-natural amino acids
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Libraries of hardly available amino acids bearing a heteroaromatic ring (2-pyrimidyl, substituted 2-pyridyl or 2-thiazolyl) at the amino group were prepared using solid-phase synthesis on various resins. The synthesized compounds are structurally similar to some known antidiabetic drugs. The paper combines features of a review (elementary introduction to the solid-phase synthesis methodology and technique for beginners and selected methods from peptide chemistry) and step-by-step experimental protocols (tested by the authors) useful as a methodic tool. The presented protocols (immobilization and modification of amino acids, placing and removal of common protective groups) require no sophisticated equipment and may be useful as pictorial introductory tasks for students education. Pleiades Publishing, Ltd., 2010.
- Babaev,Ermolat'ev
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experimental part
p. 2572 - 2589
(2011/04/15)
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- 1,8-Naphthyridine-3-carboxamide derivatives with anticancer and anti-inflammatory activity
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A number of 1-propargyl-1,8-naphthyridine-3-carboxamide derivatives (15-35) have been synthesized and screened for their in vitro cytotoxicity and anti-inflammatory activity. Compounds 22, 31 and 34 have shown high cytotoxicity against a number of cancer cell lines, while compound 24 showed significant anti-inflammatory activity.
- Kumar, Vivek,Jaggi, Manu,Singh, Anu T.,Madaan, Alka,Sanna, Vinod,Singh, Pratibha,Sharma, Pramod K.,Irchhaiya, Raghuveer,Burman, Anand C.
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experimental part
p. 3356 - 3362
(2009/10/23)
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- Succinct synthesis of β-amino acids via chiral isoxazolines
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β-Amino acids are important synthetic targets due to their presence in a wide variety of natural products, pharmaceutical agents, and mimics of protein structural motifs. While β-amino acids containing geminal substitution patterns have enormous potential for application in these contexts, synthetic challenges to the stereoselective preparation of this class of compound have thus far limited more complete studies. We present here a straightforward method employing chiral isoxazolines as key intermediates to access five different β-amino acid structural types with excellent selectivity. Of particular note is the use of this approach to prepare highly substituted cis-β-proline analogues. The ready access to these diversely substituted compounds is expected to facilitate future studies of the structure and function of this important class of molecules.
- Fuller, Amelia A.,Chen, Bin,Minter, Aaron R.,Mapp, Anna K.
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p. 5376 - 5383
(2007/10/03)
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- GLYT2 MODULATORS
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α-, β-, and γ-amino acid derivatives of formula I are disclosed as selective GlyT2 inhibitors for the treatment of central nervous system (CNS) conditions such as muscle spasticity, tinnitus, epilepsy and neuropathic pain. Formula I
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Page/Page column 52-53
(2010/02/11)
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- Highly diastereoselective and enantioselective preparation of homoallylic amines: Application for the synthesis of β-amino acids and γ-lactams
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Reactions of N-silyl- and N-aluminoimines with B- allyldiisopinocampheylborane in the presence of methanol, followed by oxidative workup furnished homoallylic amines in good yields and high ee. A 11B NMR spectroscopy study revealed that the reactions do not proceed, even at room temperature, unless a molar equivalent of water or methanol is added. The first reagent-controlled asymmetric crotylboration and alkoxyallylboration of aldimines furnishing β-methyl or βalkoxy homoallylic amines in very high diastereoselectivity and enantioselectivity are reported herein. Crotylboration and alkoxyallylboration of imines proceed only with the "allyl"-boron "ate" complexes, instead of the "allyl"-dialkylboron reagents used with aldehydes. The addition of methanol is necessary for these reactions as well. Application of this methodology for the conversion of representative nitriles to β-amino acids in two steps has been described. Additionally, a procedure for the preparation of chiral δ-amino alcohols and γ-lactams from nitriles is also reported.
- Ramachandran, P. Veeraraghavan,Burghardt, Thomas E.
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p. 4387 - 4395
(2007/10/03)
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- A concise approach to structurally diverse β-amino acids
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We have demonstrated that the high yields and selectivities of 1,3-dipolar cycloadditions can be translated into facile stereoselective syntheses of a diverse array of β-amino acids, key components of bioactive natural products, β-lactams, and peptidomimetics. Simply by selecting different combinations of three readily available starting materials (an oxime, a chiral allylic alcohol, and a nucleophile), we used the reaction sequence to prepare four different β-amino acid structural types with a variety of substitution patterns in good overall yield. Of particular note is the use of this approach to prepare highly substituted β-amino acids not readily accessible by previously reported methodologies. This will pave the way for future studies of the structure and function of this important class of molecules. Copyright
- Minter, Aaron R.,Fuller, Amelia A.,Mapp, Anna K.
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p. 6846 - 6847
(2007/10/03)
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- Phenethylamine derivatives
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The present invention has as its object providing phenethylamine derivatives that typically function as a motilin receptor antagonist and which are useful as medicines. The invention provides compounds represented by the general formula (1): (wherein A is typically an amino acid residue, R1is typically R6—CO—, R2is typically a hydrogen atom, R3is typically —CO—R7, R4is typically an alkyl group, R5is typically a hydroxyl group, R6is typically an alkyl group, and R7is typically an amino group).
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- 2,2'-dithiobisbenzamides derived from α-, β- and γ-amino acids possessing anti-HIV activities: Synthesis and structure-activity relationship
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Nucleocapsid protein (NCp7), which contains highly conserved retroviral zinc fingers, is essential in the early as well as the late phase of human immunodeficiency virus (HIV) life cycle and constitutes a novel target for AIDS therapy. HIV-1 NCp7 is a basic 55 amino acid protein containing two C(X)2C(X)4H(X)4C motif zinc fingers flanked by basic amino acids on each side. 2,2'-dithiobisbenzamides have previously been reported to release zinc from these NCp7 zinc fingers and also to inhibit HIV replication. Specifically, 2,2'-dithiobisbenzamides derived from simple amino acids showed good antiviral activities. The benzisothiazolone 3, the cyclic derivative of 2, was selected for clinical trials as an agent for AIDS therapy. Herein we report the syntheses and antiviral activities, including therapeutic indices, of 2,2'-dithiobisbenzamides derived from α-, β- and γ-amino acids. Electrospray ionization mass spectrometry was used to study the zinc-ejection activity of these compounds. Among the α-amino acid derived 2,2'-dithiobisbenzamides, analogues containing alkyl side chains were found to be antivirally active with good therapeutic indices. 2,2'-Dithiobisbenzamides, derived from β- and γ-amino acids, were found to possess better antiviral and therapeutic efficacies than the α-amino acid analogues. Thus compound 59 was found to possess an EC50 of 1.9μM with a therapeutic index of >50. Interestingly, 2,2'-dithiobisbenzamides derived from α-amino acids containing a protected acid function and polar side chains also exhibited very good antiviral activity. Copyright (C) 1998 Elsevier Science Ltd.
- Vara Prasad,Loo, Joseph A.,Boyer, Frederick E.,Stier, Michael A.,Gogliotti, Rocco D.,Turner, William J.,Harvey, Patricia J.,Kramer, Melissa R.,Mack, David P.,Scholten, Jefferey D.,Gracheck, Stephen J.,Domagala, John M.
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p. 1707 - 1730
(2007/10/03)
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- (2-Alkyl-3-pyridyl)methylpiperazine derivatives as PAF antagonists
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The present invention relates to new (2-alkyl-3-pyridyl) methylpiperazine derivatives of general formula I: wherein R1, R2 and Z are as defined in Claim 1. The invention also relates to processes for their preparation and to pharmaceutical compositions containing them. These compounds are potent, orally active PAF antagonists and, consequently, they are useful in the treatment of the diseases in which this substance is involved.
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- Intermediates of peripherally selective N-carbonyl-3,4,4-trisubstituted piperidine opioid antagonists
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Intermediates of N-carbonyl-3,4,4-substituted piperidines are provided which are useful in the preparation of peripheral opioid antagonists.
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