A scalable protocol for the synthesis and use of neomenthyldiphenylphosphine.

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemistry, 2009.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Vita.Includes bibliographical references.A scalable and reproducible protocol has been developed for the preparation of (-)- neomenthyldiphenylphosphine ((-)-1) from inexpensive starting materials. This ligand was then utilized in the nickel-catalyzed reductive coupling of alkyne 3 and aldehyde 4 to afford allylic alcohol 5 in high yield and enantiomeric excess. Several important modifications were made to the initially communicated procedure in order to effectively translate this methodology from the millimole to decimole scale. Allylic alcohol 5 was then ozonolyzed to afford [beta]-hydroxy ketone 6 with complete preservation of enantiomeric purity. Chapter II. The endo-selective cyclization of alcohols onto epoxides provides a direct route for constructing the oxygen heterocycles found in ladder polyether natural products. Additionally strategies to transform multiple epoxides into multiple new rings have appealing parallels to the proposed biogenesis of these compounds. A continuing challenge is to overcome the inherent preference for the undesired smaller ring product over the larger ring product, processes termed exo and endo cyclization, respectively. Additionally, any method to address this problem should yield products that are themselves synthetically relevant intermediates. We discovered that a benzylidene acetal templated the cyclization of electronically unbiased epoxy alcohols, such as 75, affording products with significant synthetic utility. Critical for high endo-selectivity was the use of silicon-dioxide based promoters.(cont.) Highlighting the template's utility, the newly formed product (76) was then transformed into a highly decorated THP template (84), corresponding to ring K of gymnocin A. In water, 84 underwent a waterpromoted cascade to construct three additional rings of gymnocin A. We have also achieved cascades of methylene acetal templates with electronically activated epoxides to construct the FG rings of gambierol. Use of these functionalized templates and the products derived from them sets the stage for the convergent total synthesis of ladder polyether natural products.by Aaron R. Van Dyke.Ph.D

The development of endo-selective epoxide-opening cascades in water

This tutorial review traces the development of endo-regioselective epoxide-opening reactions in water. Templated, water-promoted epoxide-opening cyclization reactions can offer rapid access to subunits of the ladder polyethers, a fascinating and complex family of natural products. This review may be of interest to those curious about the ladder polyethers and their hypothesized biogenesis, about organic reactions in water, and about the development and application of cascade reactions in organic synthesis

Bifunctional Ligands Allow Deliberate Extrinsic Reprogramming of the Glucocorticoid Receptor

Therapies based on conventional nuclear receptor ligands are extremely powerful, yet their broad and long-term use is often hindered by undesired side effects that are often part of the receptor\u27s biological function. Selective control of nuclear receptors such as the glucocorticoid receptor (GR) using conventional ligands has proven particularly challenging. Because they act solely in an allosteric manner, conventional ligands are constrained to act via cofactors that can intrinsically partner with the receptor. Furthermore, effective means to rationally encode a bias for specific coregulators are generally lacking. Using the (GR) as a framework, we demonstrate here a versatile approach, based on bifunctional ligands, that extends the regulatory repertoire of GR in a deliberate and controlled manner. By linking the macrolide FK506 to a conventional agonist (dexamethasone) or antagonist (RU-486), we demonstrate that it is possible to bridge the intact receptor to either positively or negatively acting coregulatory proteins bearing an FK506 binding protein domain. Using this strategy, we show that extrinsic recruitment of a strong activation function can enhance the efficacy of the full agonist dexamethasone and reverse the antagonist character of RU-486 at an endogenous locus. Notably, the extrinsic recruitment of histone deacetylase-1 reduces the ability of GR to activate transcription from a canonical GR response element while preserving ligand-mediated repression of nuclear factor-κB. By providing novel ways for the receptor to engage specific coregulators, this unique ligand design approach has the potential to yield both novel tools for GR study and more selective therapeutics

Basic science of osteoarthritis

Osteoarthritis (OA) is a prevalent, disabling disorder of the joints that affects a large population worldwide and for which there is no definitive cure. This review provides critical insights into the basic knowledge on OA that may lead to innovative end efficient new therapeutic regimens. While degradation of the articular cartilage is the hallmark of OA, with altered interactions between chondrocytes and compounds of the extracellular matrix, the subchondral bone has been also described as a key component of the disease, involving specific pathomechanisms controlling its initiation and progression. The identification of such events (and thus of possible targets for therapy) has been made possible by the availability of a number of animal models that aim at reproducing the human pathology, in particular large models of high tibial osteotomy (HTO). From a therapeutic point of view, mesenchymal stem cells (MSCs) represent a promising option for the treatment of OA and may be used concomitantly with functional substitutes integrating scaffolds and drugs/growth factors in tissue engineering setups. Altogether, these advances in the fundamental and experimental knowledge on OA may allow for the generation of improved, adapted therapeutic regimens to treat human OA.(undefined

Frequency drift in MR spectroscopy at 3T

Purpose: Heating of gradient coils and passive shim components is a common cause of instability in the B-0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites.Method: A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC).Results: Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p &lt; 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI.Discussion: This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.</p

Technology Integration in Chemistry Education and Research (TICER)

Aaron R. Van Dyke is a contributing author, Practical Considerations for Advancing Undergraduate Digital Literacy through Digital Laboratory Notebooks, Chapter 7: p. 107-118. Digital laboratory notebooks (DLNs), alternatively termed electronic laboratory notebooks, are valuable for cultivating digital literacy and enhancing laboratory productivity. However, selecting and implementing a DLN can be difficult. This book chapter outlines four factors to consider when selecting a DLN: cost, platform compatibility, user collaboration, and data compliance. Next, it discusses the implementation of Quip (a productivity app) as a DLN at Fairfield University, a primarily undergraduate institution. Through applications in organic chemistry, biochemistry, physical chemistry, analytical chemistry, and chemical instrumentation laboratories, the reader will gain practical knowledge of Quip’s interface, data management architecture, content creation tools, and instructor’s features. The chapter concludes by considering the legacy of accessing data within Quip and student perceptions of the DLN at Fairfield University.https://digitalcommons.fairfield.edu/chemistry-books/1003/thumbnail.jp

Eggs as Functional Foods and Nutraceuticals for Human Health

C. J. Andersen and A. R. Van Dyke are contributing authors, Modulation of Inflammation by Egg Components, Chapter 10: p. 173-197. Often described as ‘nature’s perfect food’, perceptions of egg consumption and human health have evolved substantially over the past decades, in particular dietary guidelines no longer include a limit for dietary cholesterol and recommend eggs as part of healthy eating patterns. This book presents the opportunities for processing eggs to produce value-added food, nutritional, biomedical, functional food, and nutraceutical applications. It provides new evidence around egg consumption with respect to cardiovascular diseases, metabolic syndrome, weight management, mental development, eye, muscle, and ageing health. It also highlights the new discovery regarding egg bioactives that are relevant to anti-oxidants, anti-inflammation, cardiovascular and bone health, anti-microbial and anti-viral activities. Appealing to food scientists, food chemists, researchers in human nutrition specialising in eggs and dairy nutrition, and those involved in egg production, this book is reflecting the trends and innovations in this area of research.https://digitalcommons.fairfield.edu/chemistry-books/1004/thumbnail.jp