Undergraduate GPA Predicts Biochemistry PhD Completion and Is Associated with Time to Degree.

There is interest in admission criteria that predict future success in biomedical graduate school programs, but identifying predictors of PhD attainment is inherently complex. In particular, high noncompletion rates of PhD programs have long been recognized as a major crisis. Here, we present a quantitative analysis of the PhD students enrolled in the Department of Biochemistry and Biophysics at Texas A&M University between 1980 and 2010. The input variables included sex, country of citizenship, undergraduate grade point average (GPA), and Graduate Record Examination (GRE) scores (Verbal and Quantitative Reasoning). Only GPA was a significant predictor of PhD completion based on logistic regression. We also examined associations involving nonbinary measures of success (PhD duration, first author, and total number of publications) among students who completed a PhD. GPA was again associated with the PhD duration. No enrollment variable was strongly associated with publication output. Despite potential limitations, this analysis is the first to suggest an undergraduate GPA association with PhD completion in life sciences. These results from a large state university in a predominantly rural area expand the range of programs from which such analyses have been reported.

Serine-Selective Bioconjugation.

This Communication reports the first general method for rapid, chemoselective, and modular functionalization of serine residues in native polypeptides, which uses a reagent platform based on the P(V) oxidation state. This redox-economical approach can be used to append nearly any kind of cargo onto serine, generating a stable, benign, and hydrophilic phosphorothioate linkage. The method tolerates all other known nucleophilic functional groups of naturally occurring proteinogenic amino acids. A variety of applications can be envisaged by this expansion of the toolbox of site-selective bioconjugation methods.

Electrochemically Driven, Ni-Catalyzed Aryl Amination: Scope, Mechanism, and Applications.

C-N cross-coupling is one of the most valuable and widespread transformations in organic synthesis. Largely dominated by Pd- and Cu-based catalytic systems, it has proven to be a staple transformation for those in both academia and industry. The current study presents the development and mechanistic understanding of an electrochemically driven, Ni-catalyzed method for achieving this reaction of high strategic importance. Through a series of electrochemical, computational, kinetic, and empirical experiments, the key mechanistic features of this reaction have been unraveled, leading to a second generation set of conditions that is applicable to a broad range of aryl halides and amine nucleophiles including complex examples on oligopeptides, medicinally relevant heterocycles, natural products, and sugars. Full disclosure of the current limitations and procedures for both batch and flow scale-ups (100 g) are also described.

Direct Carbon Isotope Exchange through Decarboxylative Carboxylation.

A two-step degradation-reconstruction approach to the carbon-14 radiolabeling of alkyl carboxylic acids is presented. Simple activation via redox-active ester formation was followed by nickel-mediated decarboxylative carboxylation to afford a range of complex compounds with ample isotopic incorporations for drug metabolism and pharmacokinetic studies. The practicality and operational simplicity of the protocol were demonstrated by its use in an industrial carbon-14 radiolabeling setting.

Alkyl Sulfinates: Radical Precursors Enabling Drug Discovery.

The modern constraints of drug discovery demand a rigorous validation process of all new reactions prior to widespread implementation. To this end, sulfinates (now marketed as Diversinates) have seen alacritous adoption by the medicinal chemistry community, as evidenced by the recent outpour of both patent and primary reports. Featuring more than 50 examples, this review seeks to highlight those particularly compelling cases published in the past 5 years, with an eye toward the identification of robust and predictable trends in reactivity.

Unlocking P(V): Reagents for chiral phosphorothioate synthesis.

Phosphorothioate nucleotides have emerged as powerful pharmacological substitutes of their native phosphodiester analogs with important translational applications in antisense oligonucleotide (ASO) therapeutics and cyclic dinucleotide (CDN) synthesis. Stereocontrolled installation of this chiral motif has long been hampered by the systemic use of phosphorus(III) [P(III)]-based reagent systems as the sole practical means of oligonucleotide assembly. A fundamentally different approach is described herein: the invention of a P(V)-based reagent platform for programmable, traceless, diastereoselective phosphorus-sulfur incorporation. The power of this reagent system is demonstrated through the robust and stereocontrolled synthesis of various nucleotidic architectures, including ASOs and CDNs, via an efficient, inexpensive, and operationally simple protocol.

CITU: A Peptide and Decarboxylative Coupling Reagent.

Tetrachloro-N-hydroxyphthalimide tetramethyluronium hexafluorophosphate (CITU) is disclosed as a convenient and economical reagent for both acylation and decarboxylative cross-coupling chemistries. Within the former set of reactions, CITU displays reactivity similar to that of common coupling reagents, but with increased safety and reduced cost. Within the latter, increased yields, more rapid conversion, and a simplified procedure are possible across a range of reported decarboxylative transformations.

Magnesiate Addition/Ring-Expansion Strategy To Access the 6-7-6 Tricyclic Core of Hetisine-Type C20-Diterpenoid Alkaloids.

A synthetic strategy to access the fused 6-7-6 tricyclic core of hetisine-type C20-diterpenoid alkaloids is reported. This strategy employs a Diels-Alder cycloaddition to assemble a fused bicyclic anhydride intermediate, which is elaborated to a vinyl lactone-acetal bearing an aromatic ring in five steps. Aromatic iodination is followed by magnesium-halogen exchange with a trialkyl magnesiate species, which undergoes intramolecular cyclization. Subsequent oxidation provides the desired 6-7-6 tricyclic diketoaldehyde, with carbonyl groups at all three positions for eventual C-N bond formation and subsequent elaboration.

Residue-Specific Peptide Modification: A Chemist's Guide.

Advances in bioconjugation and native protein modification are appearing at a blistering pace, making it increasingly time consuming for practitioners to identify the best chemical method for modifying a specific amino acid residue in a complex setting. The purpose of this perspective is to provide an informative, graphically rich manual highlighting significant advances in the field over the past decade. This guide will help triage candidate methods for peptide alteration and will serve as a starting point for those seeking to solve long-standing challenges.

Peptide Macrocyclization Inspired by Non-Ribosomal Imine Natural Products.

A thermodynamic approach to peptide macrocyclization inspired by the cyclization of non-ribosomal peptide aldehydes is presented. The method provides access to structurally diverse macrocycles by exploiting the reactivity of transient macrocyclic peptide imines toward inter- and intramolecular nucleophiles. Reactions are performed in aqueous media, in the absence of side chain protecting groups, and are tolerant of all proteinogenic functional groups. Macrocyclic products bearing non-native and rigidifying structural motifs, isotopic labels, and a variety of bioorthogonal handles are prepared, along with analogues of four distinct natural products. Structural interrogation of the linear and macrocyclic peptides using variable-temperature NMR and circular dichroism suggests that preorganization of linear substrates is not a prerequisite for macrocyclization.

The taumycin A macrocycle: asymmetric total synthesis and revision of relative stereochemistry.

The first asymmetric total synthesis and revision of the relative configuration of the 12-membered taumycin A macrocycle is described. Key to the success of this work was a novel α-keto ketene macrocyclization that provided an efficient means by which to access two diastereomers of the desired macrolide without the need to employ additional coupling agents or unnecessary oxidation state adjustments.