Putting “umpolung” to work in synthesis of nitrogen-bearing stereocenters

Professor Li Deng‘s lab in the Brandeis Chemistry Department has recently published a high-profile paper in Nature, disclosing an important advance in the chemical synthesis of organic molecules containing nitrogen. Li Deng writeup 1

A great number of important drugs contain at least one nitrogen atom connected to a “stereogenic” carbon atom. Stereogenic carbons are connected to four different groups, making possible two different configurations called “R-” or “S-”. In synthesizing a drug, it can be disastrous if the product does not have the correct R/S configuration.  For instance, the morning-sickness drug Thalidomide caused birth defects in ~10,000 children because it was a mixture of R and S molecules.Li Deng writeup 2

Selective preparation of only R or only S molecules containing nitrogen is a major challenge in organic chemistry. Many recent approaches have formed such stereocenters by use of an electron rich “nucleophile” to attack an electron poor “imine”. Deng is now the first to report an unconventional strategy in which the polarity of the reaction partners is reversed. In the presence of base and a creatively designed catalyst, the imine is converted into an electron rich nucleophile, and can attack a variety of electrophiles. Deng’s catalysts are effective in minute quantities (as low as 0.01 % of the reaction mixture), and yield products with R- or S- purities of 95-98 %.

In addition to Professor Deng, authors on the paper included former graduate student Yongwei Wu PhD ’14, current Chemistry PhD student Zhe Li, and Chemistry postdoctoral associate Lin Hu.

Wu Y, Hu L, Li Z, Deng L. Catalytic asymmetric umpolung reactions of imines. Nature. 2015;523(7561):445-50. (commentary)

Snider named ACS Fellow

Charles A. Breskin Professor of Organic Chemistry Barry Snider has been named a Fellow by the American Chemical Society (ACS). ACS members are selected as fellows to recognize and honor their outstanding achievements in and contributions to science, the profession, and ACS. Fellows will be inducted at the ACS National Meeting in Denver on Aug. 29. Snider’s work in recent years has focused on total synthesis of natural products, a dazzling array of which are shown on his website: Recent stories on this blog discussing new syntheses from the Snider lab include:



Biomimetic Route to Maldoxin

In their recent Organic Letters paper entitled the Syntheses of Chloroisosulochrin and Isosulochrin and Biomimetic Elaboration to Maldoxin, Maldoxone, Dihydromaldoxin, and Dechlorodihydromaldoxin, the Snider lab at Brandeis developed an efficient biomimetic synthesis of maldoxin (4), the biological precursor of several cytotoxic natural products recently isolated from the plant endophytic fungus Pestalotiopsis fici. Chloroisosulochrin (1) was synthesized for the first time and elaborated to maldoxin (4) by a three-step biomimetic route consisting of oxidative cyclization to give spirofuranone 2, acid catalyzed ring opening to yield dihydromaldoxin (3) and a second oxidative cyclization to form maldoxin (4).

Electrophilic chlorination of phenols usually takes place unselectively at both ortho and para positions.  For the synthesis of chloroisosulochrin, they developed an ortho selective chlorination using 2,2,6,6-tetramethylpiperidine and sulfuryl chloride.  Presumably a hindered N-chloroamine is formed, which hydrogen bonds to the phenol and delivers electrophilic chlorine intramolecularly.

Separating proteins and manipulating live cells using magnetic nanoparticles

Brandeis grad students Yue Pan (Chemistry) and Marcus Long (Biochemistry), together with Professors Lizbeth Hedstrom and Bing Xu, have synthesized novel 6 nm diameter magnetic nanobeads (comparable in size to a globular protein) and used them to separate specific proteins from a cell lysate and manipulate live cells. This work has just appeared online in the journal Chemical Science.

Selectively binding glutathione-S-transferase fusion proteins using
glutathione-decorated iron oxide nanoparticles and down-stream applications

These small, magnetic beads have numerous advantages over larger traditional glutathione-modified beads, including rapid purification, and ultra low non-specific binding. Importantly, both the purified GST and the protein of interest (POI) preserve their innate properties. They also demonstrate that functionalized iron oxide nanoparticles can be used to manipulate live cells. This work  establishes design principles for decorating magnetic nanoparticles that will ultimately should lead to a general and comprehensive platform for studying biological interactions and biological systems using a magnetic force.

An alternative to scuba diving

Many promising medicinal agents (anti-cancer, anti-bacterial, anti-viral and anti-fungal) have been discovered among the diverse molecules produced by marine organisms. However, scuba-diving to harvest sponges and algae is not usually a practical way of obtaining usable quantities of these compounds, especially if they are present only in trace quantities in the source organisms.

A recently published paper in Organic Letters from the laboratory of Assistant Professor of Chemistry Isaac Krauss is the first to present a synthetic laboratory approach to the preparation of the bromophycolides, originally isolated from Callophycus Serratus, a red algae which was collected off the coast of Fiji. Although these compounds were shown to posses anti-tumour, anti-HIV and anti-malarial properties, algae collected in a second expedition to Fiji apparently contained none of the natural product (hence the desirability of a laboratory synthesis). The bromophycolides are a structurally unique family of natural products containing brominated asymmetric carbon centers and large 19-membered rings. This paper illustrates the preparation of the bromophycolide A and D ring system in high enantiomeric purity via a short (9-step) synthetic sequence.

Thomas named 2011 Sloan Research Fellow

Assistant Professor of Chemistry Christine Thomas has been named a 2011 Sloan Research Fellow. These two-year fellowships are awarded to early-career scientists in recognition of distinguished performance and a unique potential to make substantial contributions to their field. Research in the Thomas laboratory focuses on the design and synthesis of new transition metal complexes to examine the fundamental interactions between different components of bifunctional catalysts with the ultimate goal of uncovering new transition-metal catalyzed bond activation processes related to renewable energy. Since starting in the Chemistry department at Brandeis in 2008, Thomas and coworkers have developed a series of bimetallic catalysts that utilize metal-metal interactions to attenuate redox potentials and promote the activation of small molecules such as hydrogen, alkyl halides, and carbon dioxide.

The Thomas lab has an energetic and talented team of researchers

Arne Ekstrom ’96, PhD ’04 and Mikhail Ershov MA ’00 were also named as 2011 Sloan Research Fellows. Ekstrom received a B.A. in Biology and Psychology from Brandeis, and after getting an M.S. at U. Arizona, returned and completed a Ph.D. in Neuroscience here in 2004, working with Michael Kahana. After a postdoc at UCLA, Arne took a position as an Assistant Professor in the Center for Neuroscience at U. California, Davis. His lab studies spatial memory using EEG and fMRI techniques. Ershov came to Brandeis from Moscow State Univ. and received an MA in Math in 2000 bofore going on to Ph.D. work at Yale and a faculty position at U. Virginia. Ershov is being recognized for research contributions to various aspects of group theory.

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