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1.
Chemistry ; 28(6): e202103269, 2022 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-34704653

RESUMEN

Mixed TMP-bases (TMP=2,2,6,6-tetramethylpiperidyl), such as TMPMgCl ⋅ LiCl, TMP2 Mg ⋅ 2LiCl, TMPZnCl ⋅ LiCl and TMP2 Zn ⋅ 2LiCl, are outstanding reagents for the metalation of functionalized aromatics and heterocycles. In the presence of Lewis acids, such as BF3 ⋅ OEt2 or MgCl2 , the metalation scope of such bases was dramatically increased, and regioselectivity switches were achieved in the presence or absence of these Lewis acids. Furthermore, highly reactive lithium bases, such as TMPLi or Cy2 NLi, are also compatible with various Lewis acids, such as MgCl2 ⋅ 2LiCl, ZnCl2 ⋅ 2LiCl or CuCN ⋅ 2LiCl. Performing such metalations in continuous flow using commercial setups permitted practical and convenient reaction conditions.

2.
Chemistry ; 27(56): 13977-13981, 2021 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-34387898

RESUMEN

The continuous flow reaction of various aryl or heteroaryl bromides in toluene in the presence of THF (1.0 equiv) with sec-BuLi (1.1 equiv) provided at 25 °C within 40 sec the corresponding aryllithiums which were acylated with various functionalized N,N-dimethylamides including easily enolizable amides at -20 °C within 27 sec, producing highly functionalized ketones in 48-90 % yield (36 examples). This method was well suited for the preparation of α-chiral ketones such as naproxene and ibuprofen derived ketones with 99 % ee. A one-pot stepwise bis-addition of two different lithium organometallics to 1,1,3,3-tetramethyurea (TMU) provided unsymmetrical ketones in 69-79 % yield (9 examples).


Asunto(s)
Tolueno , Compuestos de Metilurea
3.
Chemistry ; 23(53): 13046-13050, 2017 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-28777497

RESUMEN

A set of successive regioselective metalations and functionalizations of the 1,5-naphthyridine scaffold are described. A combination of Zn-, Mg-, and Li-TMP (TMP=2,2,6,6-tetramethylpiperidyl) bases and the presence or absence of a Lewis acid (BF3 ⋅OEt2 ) allows the introduction of up to three substituents to the 1,5-naphthyridine core. Also, a novel "halogen dance" reaction was discovered upon metalation of an 8-iodo-2,4-trifunctionalized 1,5-naphthyridine allowing a fourth regioselective functionalization. Additionally, reactions leading to key 1,5-naphthyridines for the preparation of OLED materials and a potential antibacterial agent were performed.

4.
Proc Natl Acad Sci U S A ; 106(49): 20740-5, 2009 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-19933333

RESUMEN

We used single-molecule FRET in combination with other biophysical methods and molecular simulations to investigate the effect of temperature on the dimensions of unfolded proteins. With single-molecule FRET, this question can be addressed even under near-native conditions, where most molecules are folded, allowing us to probe a wide range of denaturant concentrations and temperatures. We find a compaction of the unfolded state of a small cold shock protein with increasing temperature in both the presence and the absence of denaturant, with good agreement between the results from single-molecule FRET and dynamic light scattering. Although dissociation of denaturant from the polypeptide chain with increasing temperature accounts for part of the compaction, the results indicate an important role for additional temperature-dependent interactions within the unfolded chain. The observation of a collapse of a similar extent in the extremely hydrophilic, intrinsically disordered protein prothymosin alpha suggests that the hydrophobic effect is not the sole source of the underlying interactions. Circular dichroism spectroscopy and replica exchange molecular dynamics simulations in explicit water show changes in secondary structure content with increasing temperature and suggest a contribution of intramolecular hydrogen bonding to unfolded state collapse.


Asunto(s)
Transferencia Resonante de Energía de Fluorescencia/métodos , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/metabolismo , Pliegue de Proteína , Precursores de Proteínas/química , Precursores de Proteínas/metabolismo , Temperatura , Timosina/análogos & derivados , Guanidina/farmacología , Interacciones Hidrofóbicas e Hidrofílicas , Simulación de Dinámica Molecular , Desnaturalización Proteica/efectos de los fármacos , Pliegue de Proteína/efectos de los fármacos , Estructura Secundaria de Proteína , Análisis Espectral , Timosina/química , Timosina/metabolismo
5.
Chem Sci ; 12(17): 6143-6147, 2021 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-33996011

RESUMEN

A new regioselective 3,4-difunctionalization of 3-chloropyridines via 3,4-pyridyne intermediates is reported. Regioselective lithiation of 3-chloro-2-ethoxypyridine and a related 2-thio-derivative followed by treatment with aryl- and alkylmagnesium halides as well as magnesium thiolates at -78 °C produced 3,4-pyridynes during heating to 75 °C. Regioselective addition of the Grignard moiety in position 4 followed by an electrophilic quench in position 3 led to various 2,3,4-trisubstituted pyridines. This method was adapted into a continuous flow set-up. As an application, we have prepared a key intermediate for (±)-paroxetine.

6.
Org Lett ; 22(2): 493-496, 2020 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-31886671

RESUMEN

A selective acylation of readily accessible organomagnesium reagents with commercially available esters proceeds at convenient temperatures and short residence times in continuous flow. Flow conditions allow us to prevent premature collapse of the hemiacetal intermediates despite noncryogenic conditions, thus furnishing ketones in good yields. Throughout, the coordinating ability of the ester and/or Grignard was crucial for the reaction outcome. This was leveraged by the obtention of several bisaryl ketones using 2-hydroxy ester derivatives as substrates.

7.
Org Lett ; 20(24): 8057-8060, 2018 12 21.
Artículo en Inglés | MEDLINE | ID: mdl-30511876

RESUMEN

The amination of various phosphorodiamidate-substituted pyridines, quinolines, and quinoxaline with magnesium amides R2NMgCl·LiCl proceeds at room temperature within 8 h. Several pharmaceutically active amines were suitable substrates for this amination procedure, and also the antihistaminic tripelennamine was prepared. Additionally, several heterocyclic phosphorodiamidates underwent directed ortho-metalation (D oM) using TMPMgCl·LiCl (TMP = 2,2,6,6-tetramethylpiperidyl) or TMP2Mg·2LiCl, followed by electrophilic functionalization prior to the amination step, which led to ortho-functionalized aminated N-heterocycles.

8.
J Occup Environ Med ; 52(6): 635-46, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20523235

RESUMEN

OBJECTIVE: To compare the performance of predictive models based on health care claims, health risk assessment (HRA), or both in prospectively identifying high-cost individuals with chronic conditions. METHODS: Participants included 8056 employees who completed an HRA and were enrolled in a health plan for at least 6 months during the 36-month study period. Two-stage multivariate regression identified predictors of claims cost in four age-by-gender groups. RESULTS: All models predicted costs effectively, but the combined model performed better (R2 = 0.198 to 0.309) than either the claims-based (R2 = 0.168 to 0.263) or HRA-based model (R2 = 0.125 to 0.205). CONCLUSION: An HRA-based predictive model appears to be a reasonable alternative to claims-based predictive models for identifying individuals for chronic condition management outreach. Where practical, a combined model offers advantages of both approaches and meaningfully increases accuracy.


Asunto(s)
Enfermedad Crónica/economía , Indicadores de Salud , Modelos Estadísticos , Adulto , Análisis Costo-Beneficio , Costos de la Atención en Salud , Gastos en Salud , Humanos , Revisión de Utilización de Seguros/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Estudios Prospectivos
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