A hidden catalysis: metal-, and organocatalyst-free one-pot assembly of chiral aza-tricyclic molecules

<p></p><p> Development of a rapid synthesis of complex molecules from simple building blocks under a metal-and organocatalyst-free condition is both conceptually and chemically challenging. Here, we developed a hidden catalysis that allow the straightforward assembly of enantiopure aza-tricyclic molecules containing six contiguous stereocenters from <a>aminophenols, α,β-unsaturated aldehydes </a>and α-amino acids. <a>Without using a metal or an organocatalyst, our approach relies on a temporary formation of a spiroimidazolidinone intermediate and its participation in a sequential aza-Michael/Michael reaction as both a substrate and a catalyst</a> under an iminium/enamine catalysis. The formation of the putative iminium intermediate was supported by spectroscopic data and its interruptive reduction derivative was isolated and fully characterized. Whereas a conventional catalyst is always present and does not undergo a permanent chemical change in a classic catalysis, the spiroimidazolidinone intermediate is conceptualized as a sub-catalyst as it is only temporary produced from precursors and catalyzes its own consumption. This unique substrate-catalyst (sub-catalyst) dual role of the spiroimidazolidinone induces a substantial steric discrimination in the transition state and an excellent overall diastereoselectivity (>20:1 dr). It allows the use of an amino acid precursor as the sole chirality genesis and avoids the use of transition metals or organocatalysts. An enantiomer of an aza-tricyclic imidazolidinone can be prepared from a commercially available amino acid precursor. The aqueous-based reaction is practical and scalable for multi-gram synthesis. The success of implementing this sub-catalysis concept in the synthesis will pave the way for many efficient chiral catalyst-free preparations of chiral complex molecules.<br></p><br><p></p>

Synthesis and Characterization of a Novel Biheterocyclic -amino Acid Precursor of the Triazole-Tetrazole Type, via the Copper (I) Catalyzed Alkyne-Azide Cycloaddition Reaction (CuAAC)

In this paper, we describe the regioselective synthesis of a novel tri-heterocyclic compound, a biheterocyclic amino acid precursor, derived from both triazole and tetrazole. The key step of our synthesis approach was the Huigsen 1,3-dipolar cycloaddition reaction, catalyzed by the copper (I) formed in situ by reduction of Cu(II) salts (CuSO4), 5H2O) by sodium ascorbate, and using as dipole the oxazoline azide derivative 4-(azidomethyl)-4-ethyl-2-phenyl-4,5-dihydrooxazole (4) and as dipolarophile 5-(4-methoxyphenyl)-2-(prop-2-yn-1-yl)-2H-tetrazole (3). The Cu(I) catalysis allowed us to carry out the cycloaddition at room temperature during a reaction time of only 8 hours and also to selectively obtain the 1,4-regioisomer; one of the two possible isomers, with a yield of 90% after chromatography on a silica gel column (ether/hexane: 1/2), and recrystallization in an ether/acetone mixture. The desired compound, 4-ethyl-4-((4-((5-(4-methoxyphenyl)-2H-tetrazol-2-yl)methyl)-1H-1,2,3-triazol-1-yl)methyl)-2-phenyl-4,5-dihydrooxazole (5) was analyzed by 1D magnetic resonance spectroscopy (1H, 13C), and characterized physico-chemically by mass spectrometry and elemental analysis.

Unleashing the shape of L-DOPA at last

Herein, we report the first rotational study of neutral L-DOPA, an extensively used supramolecular synthon and an amino acid precursor of the neurotransmitters dopamine, norepinephrine (noradrenaline), and epinephrine (adrenaline) using...

Cloning, characterisation and expression profile of kisspeptin1 and the kisspeptin1 receptor in the hypothalamic–pituitary–ovarian axis of Chinese alligator Alligator sinensis during the reproductive cycle

Kisspeptin1 (Kiss1), a product of the Kiss1 gene, plays an important role in the regulation of reproduction in vertebrates by activating the Kiss1 receptor (Kiss1R) and its coexpression with gonadotrophin-releasing hormone (GnRH) in GnRH neurons. The purpose of this study was to clone the Kiss1 and Kiss1R genes found in the brain of Alligator sinensis and to explore their relationship with reproduction. The full-length cDNA of Kiss1 is 816bp, the open reading frame (ORF) is 417bp and the gene encodes a 138-amino acid precursor protein. The full-length cDNA of Kiss1R is 2348bp, the ORF is 1086bp and the gene encodes a 361-amino acid protein. Quantitative polymerase chain reaction showed that, except for Kiss1R expression in the hypothalamus, the expression of Kiss1 and Kiss1Rduring the reproductive period of A. sinensis was higher than that in the hypothalamus, pituitary gland and ovary during the hibernation period. The changes in GnRH2 mRNA in the hypothalamus were similar to those of GnRH1 and peaked during the reproductive period. This study confirms the existence of Kiss1 and Kiss1R in A. sinensis and the findings strongly suggest that Kiss1 and Kiss1R may participate in the regulation of GnRH secretion in the hypothalamus of alligators during the reproductive period. Furthermore, this is the first report of the full-length cDNA sequences of Kiss1 and Kiss1R in reptiles.

Apelin receptor (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The apelin receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the apelin receptor [68]) responds to apelin, a 36 amino-acid peptide derived initially from bovine stomach. apelin-36, apelin-13 and [Pyr1]apelin-13 are the predominant endogenous ligands which are cleaved from a 77 amino-acid precursor peptide (APLN, Q9ULZ1) by a so far unidentified enzymatic pathway [80]. A second family of peptides discovered independently and named Elabela [11] or Toddler, that has little sequence similarity to apelin, is present, and functional at the apelin receptor in the adult cardiovascular system [87, 67]. Structure-activity relationship Elabela analogues have been described [61].

Improvement of Sperm Motility of Rainbow Trout (Oncorhynchus mykiss W., 1792) by Supplementation of L-Arginine

In this study, the effect of supplementing amino acid-precursor of nitric oxide (NO) L-arginine were examined on sperm motility of rainbow trout Oncorhynchus mykiss. Different concentrations [0 mM (Control), 1 mM, 2 mM, 4 mM and 8 mM] of L-arginine were used in the study. To assess the effects on percentage of motile sperm and longevity, L-arginine was added to activation medium containing NaCl (52 mM). The higher L-arginine concentration (4mM) has promoting-effect on sperm motility. The treatments containing L-arginine caused significant effect on percentage of motile sperm and longevity. Overall, the findings of the present study indicated that supplementation of L-arginine may have improving effects on sperm motility of rainbow trout.

Procalcitonin

Procalcitonin (PCT) is the 116 amino acid precursor of the hormone calcitonin, produced by the C cells of the thyroid. Its synthesis is upregulated in bacterial infection and downregulated by viral infection. Consequently, with the increasing development of antibiotic resistance, interest has focused on the ability of this marker to not only diagnose infection but to tailor antibiotic treatment and help reduce the development of antibiotic resistance. The value of PCT depends on the specific clinical situation and pretest probability of disease. This article discusses the role of PCT in these different situations, namely primary care, the emergency department and the intensive care unit. The true cost effectiveness of this test remains difficult to prove as evidence for the potential impact of using PCT on slowing the development of bacterial resistance remains largely circumstantial.

Organocatalyzed C–C Ring Construction: The Hayashi Synthesis of PGE1 Me Ester

Xiaohua Liu and Xiaoming Feng of Sichuan University devised (J. Org. Chem. 2013, 78, 6322) a catalyst that mediated the addition of the ylide 2 to the enone 1 to give 3. Peng-fei Xu of Lanzhou University found (Chem. Commun. 2013, 49, 4625) that the vinyl pyrrole 4 was sufficiently nucleophilic to add to 5, leading to the cyclobutane 6. Albert Moyano of the Universitat de Barcelona added (Eur. J. Org. Chem. 2013, 3103) 8 to the unsaturated aldehyde 7 to give the β-amino acid precursor 9. Eugenia Marqués-López and Mathias Christmann, now at Freie Universität Berlin effected (Synthesis 2013, 45, 1016) the intramolecular Michael cyclization of 10 to give 11. Delong Liu and Wanbin Zhang of Shanghai Jiao Tong University showed (Synthesis 2013, 45, 1612) that 12 and 13 could be combined to give the cyclopentane 14. Ismail Ibrahem and Armando Córdova of Mid Sweden University combined (Angew. Chem. Int. Ed. 2013, 52, 6050) 15 and 16 to give 17, with good control of the quaternary center. Kamal Nain Singh of Panjab University prepared (Synthesis 2013, 45, 1406) a proline-derived sulfoxide that mediated the addition of cyclohexanone 18 to 19. Intramolecular aldehyde alkylation is underdeveloped as a synthetic method. David W.C. MacMillan of Princeton University established (J. Am. Chem. Soc. 2013, 135, 9358) a single-electron transfer variant, cyclizing 21 to 22. Arianna Quintavalla of the University of Bologna effected (Adv. Synth. Catal. 2013, 355, 938) the double addition of nitromethane 24 to 23 to give 25. John Cong-Gui Zhao of the University of Texas at San Antonio reported (Chem. Eur. J. 2013, 19, 1666; J. Org. Chem. 2013, 78, 4153) parallel results (not pictured) with aryl enones as the acceptors. Bor-Cherng Hong of the National Chung Cheng University condensed (Eur. J. Org. Chem. 2013, 2472) 26 with the alcohol 27 to give 28. Again, good control of the quaternary center was observed. Marc C. Kimber of Loughborough University used (J. Org. Chem. 2013, 78, 3476) an organocatalyst to rearrange the prochiral endoperoxide 29 to the hydroxy enone, to which malonate 30 was added to give 31.

Discovery of a Novel Functional Leptin Protein (LEP) in Zebra Finches: Evidence for the Existence of an Authentic Avian Leptin Gene Predominantly Expressed in the Brain and Pituitary

Leptin (LEP) is reported to play important roles in controlling energy balance in vertebrates, including birds. However, it remains an open question whether an authentic “LEP gene” exists and functions in birds. Here, we identified and characterized a LEP gene (zebra finch LEP [zbLEP]) encoding a 172-amino acid precursor in zebra finches. Despite zbLEP showing limited amino acid sequence identity (26%–29%) to human and mouse LEPs, synteny analysis proved that zbLEP is orthologous to mammalian LEP. Using a pAH32 luciferase reporter system and Western blot analysis, we demonstrated that the recombinant zbLEP protein could potently activate finch and chicken LEP receptors (zbLEPR; cLEPR) expressed in human embryonic kidney 293 cells and enhance signal transducer and activator of transcription 3 phosphorylation, further indicating that zbLEP is a functional ligand for avian LEPRs. Interestingly, quantitative real-time RT-PCR revealed that zbLEP mRNA is expressed nearly exclusively in the pituitary and various brain regions but undetectable in adipose tissue and liver, whereas zbLEPR mRNA is widely expressed in adult finch tissues examined with abundant expression noted in pituitary, implying that unlike mammalian LEP, finch LEP may not act as an adipocyte-derived signal to control energy balance. As in finches, a LEP highly homologous to zbLEP was also identified in budgerigar genome. Strikingly, finch and budgerigar LEPs show little homology with chicken LEP (cLEP) previously reported, suggesting that the so-called cLEP is incorrect. Collectively, our data provide convincing evidence for the existence of an authentic functional LEP in avian species and suggest an important role of brain- and pituitary-derived LEP played in vertebrates.