Native N-glycopeptide thioester synthesis through N→S acyl transfer.

Peptide thioesters are important tools for the total synthesis of proteins using native chemical ligation (NCL). Preparation of glycopeptide thioesters, that enable the assembly of homogeneously glycosylated proteins, is complicated by the perceived fragile nature of the sugar moiety. Herein, we demonstrate the compatibility of thioester formation via N→S acyl transfer with native N-glycopeptides and report observations that will aid in their preparation.

Maternal goals for childbirth associated with planned vaginal and planned cesarean birth.

We describe maternal childbirth goals among women planning either cesarean or vaginal birth. Women in the third trimester planning cesarean or vaginal birth were asked to report up to five childbirth goals. Goal achievement was assessed postpartum.

Embryonic toxin expression in the cone snail Conus victoriae: primed to kill or divergent function?

Predatory marine cone snails (genus Conus) utilize complex venoms mainly composed of small peptide toxins that target voltage- and ligand-gated ion channels in their prey. Although the venoms of a number of cone snail species have been intensively profiled and functionally characterized, nothing is known about the initiation of venom expression at an early developmental stage. Here, we report on the expression of venom mRNA in embryos of Conus victoriae and the identification of novel α- and O-conotoxin sequences.

Enantioselective α-arylation of aldehydes via the productive merger of iodonium salts and organocatalysis.

The enantioselective α-arylation of aldehydes has been accomplished using diaryliodonium salts and a combination of copper and organic catalysts. These mild catalytic conditions provide a new strategy for the enantioselective construction and retention of enolizable α-formyl benzylic stereocenters, a valuable synthon for the production of medicinal agents. As one example, this new asymmetric protocol has been applied to the rapid synthesis of (S)-ketoprofen, a commercially successful oral and topical analgesic.

Mothers' satisfaction with planned vaginal and planned cesarean birth.

We sought to describe maternal satisfaction with childbirth among women planning either cesarean or vaginal birth. We enrolled primiparous women planning cesarean birth and a comparison group planning vaginal birth. After delivery, the maternal subjective experience was assessed with a visual analogue satisfaction scale and the Salmon questionnaire, with scale scores for these aspects of the maternal experience of birth: fulfillment, distress, and difficulty.

Enantioselective organocatalytic α-fluorination of cyclic ketones.

The first highly enantioselective α-fluorination of ketones using organocatalysis has been accomplished. The long-standing problem of enantioselective ketone α-fluorination via enamine activation has been overcome via high-throughput evaluation of a new library of amine catalysts. The optimal system, a primary amine functionalized Cinchona alkaloid, allows the direct and asymmetric α-fluorination of a variety of carbo- and heterocyclic substrates.

Total synthesis of diazonamide A.

A total synthesis of the marine natural product diazonamide A (1) has been accomplished. This work features a highly stereoselective synthesis of the C(10) quaternary center and the central furanoindoline core enabled by an iminium-catalyzed alkylation-cyclization cascade. Additionally, a magnesium-mediated intramolecular macroaldolization and a palladium-catalyzed tandem borylation/annulation were developed to enable the closure of the two 12-membered macrocycles of diazonamide A.

Semi-synthesis of glycoproteins from E. coli through native chemical ligation.

Sufficient quantities of homogeneous samples of post-translationally modified proteins are often not readily available from biological sources to facilitate structure-function investigations. Native chemical ligation (NCL) is a convenient method for the production of biologically active proteins from smaller fragments. Such an approach allows protein modifications to be introduced in a controlled fashion into smaller peptide fragments which are amenable to total chemical synthesis.

Organocatalysis.

The use of small-molecule organic catalysts in organic synthesis has flourished over the past decade. Examples of defining concepts and cutting-edge results are provided in the papers in this Special Feature.

Direct and enantioselective {alpha}-allylation of ketones via singly occupied molecular orbital (SOMO) catalysis.

The first enantioselective organocatalytic α-allylation of cyclic ketones has been accomplished via singly occupied molecular orbital catalysis. Geometrically constrained radical cations, forged from the one-electron oxidation of transiently generated enamines, readily undergo allylic alkylation with a variety of commercially available allyl silanes. A reasonable latitude in both the ketone and allyl silane components is readily accommodated in this new transformation.

Access to phosphoproteins and glycoproteins through semi-synthesis, Native Chemical Ligation and N→S acyl transfer.

Peptide thioesters are important tools for protein synthesis and semi-synthesis through their use in Native Chemical Ligation (NCL). NCL can be employed to assemble site-specifically modified proteins that can help elucidate the mechanisms of biomolecular processes. In this article we explore the compatibility of phosphopeptide synthesis and glycopeptide synthesis with thioester production through N→S acyl transfer.

Enantioselective α-benzylation of aldehydes via photoredox organocatalysis.

The first enantioselective aldehyde α-benzylation using electron-deficient aryl and heteroaryl substrates has been accomplished. The productive merger of a chiral imidazolidinone organocatalyst and a commercially available iridium photoredox catalyst in the presence of household fluorescent light directly affords the desired homobenzylic stereogenicity in good to excellent yield and enantioselectivity. The utility of this methodology has been demonstrated via rapid access to an enantioenriched drug target for angiogenesis suppression.

Fireground use of an emergency escape respirator.

Introduction: Firefighters who become lost, disoriented, or trapped in a burning building may die after running out of air in their self-contained breathing apparatus (SCBA). An emergency escape device has been developed that attaches to the firefighter's mask in place of the SCBA regulator. The device filters out particulate matter and a number of hazardous components of smoke (but does not provide oxygen), providing additional time to escape after the firefighter runs out of SCBA air.

Concerning the mechanism of the FeCl3-catalyzed alpha-oxyamination of aldehydes: evidence for a non-SOMO activation pathway.

The mechanism of a recently reported aldehyde alpha-oxyamination reaction has been studied using a combination of kinetic, spectrometric, and spectrophotometric techniques. Most crucially, the use of a validated cyclopropane-based radical-clock substrate has demonstrated that carbon-oxygen bond formation occurs predominantly through an enamine activation manifold. The mechanistic details reported herein indicate that, as has been proposed for previously studied alcohol oxidations, complexation between TEMPO and a simple metal salt leads to electrophilic ionic reactivity.

Enantioselective organo-SOMO cascade cycloadditions: a rapid approach to molecular complexity from simple aldehydes and olefins.

A highly selective, radical-mediated (4 + 2) coupling reaction of aldehydes and conjugated olefins has been achieved through asymmetric SOMO-catalysis. A radical-polar crossover mechanism is proposed wherein olefin addition to a transient enamine radical cation and oxidation of the resulting radical furnishes a cation which is vulnerable to nucleophilic addition. A range of aromatic aldehydes are shown to couple with styrenes and dienes to provide cyclic products with high chemical efficiency, regioselectivity, and stereoselectivity.

Towards biomolecular assembly employing extended native chemical ligation in combination with thioester synthesis using an N-->S acyl shift.

The advent of kinetically controlled Native Chemical Ligation has permitted more efficient sequential Native Chemical Ligation reactions to take place in one pot where one or more of the peptide fragments contains an N-terminal cysteine residue and a C-terminal thioester. The reactivity of the thioester component can dictate how fragments behave through careful choice of leaving group (alkyl or aryl thiol) and the C-terminal amino acid residue. Although thioester reactivity is exquisitely controlled, reactivity of the N-terminal cysteine residue has been curbed using protecting groups, usually the thiazolidine-4-carboxo (Thz) group as it can be removed in the presence of the thioester at acidic pH.

The phospholipase C inhibitor U-73122 inhibits Ca(2+) release from the intracellular sarcoplasmic reticulum Ca(2+) store by inhibiting Ca(2+) pumps in smooth muscle.

Background And Purpose: The sarcoplasmic reticulum (SR) releases Ca(2+) via inositol 1,4,5-trisphosphate receptors (IP(3)R) in response to IP(3)-generating agonists. Ca(2+) release subsequently propagates as Ca(2+) waves. To clarify the role of IP(3) production in wave generation, the contribution of a key enzyme in the production of IP(3) was examined using a phosphoinositide-specific phospholipase C (PI-PLC) inhibitor, U-73122.

The organocatalytic three-step total synthesis of (+)-frondosin B.

The frondosins are a family of marine sesquiterpenes isolated from the sponge Dysidea frondosa that exhibit biological activities ranging from anti-inflammatory properties to potential application in anticancer and HIV therapy. Herein, a concise enantioselective total synthesis of (+)-frondosin B is described which requires a total of three chemical steps. The enantioselective conjugate addition of a benzofuran-derived boronic acid to crotonaldehyde in the presence of an imidazolidinone organocatalyst builds the critical stereogenic center of frondosin B in the first operation, while the remaining two ring systems of this natural product are installed in the two subsequent steps.

In situ detection of pterins by SERS.

Surface enhanced Raman scattering (SERS) has been used to detect specific pterin molecules at sub-nanomolar concentrations. SERS is fast becoming a widely used technique for the sensitive and specific detection of multiple analytes. The information-rich and concentration-dependent spectra obtained from SERS make the technique ideally placed for high speed, low cost analysis of almost any analyte.

Agonist-evoked Ca(2+) wave progression requires Ca(2+) and IP(3).

Smooth muscle responds to IP(3)-generating agonists by producing Ca(2+) waves. Here, the mechanism of wave progression has been investigated in voltage-clamped single smooth muscle cells using localized photolysis of caged IP(3) and the caged Ca(2+) buffer diazo-2. Waves, evoked by the IP(3)-generating agonist carbachol (CCh), initiated as a uniform rise in cytoplasmic Ca(2+) concentration ([Ca(2+)](c)) over a single though substantial length (approximately 30 microm) of the cell.

Peptide and protein thioester synthesis via N-->S acyl transfer.

Peptide and protein thioesters are playing an increasingly prominent role in the chemical toolbox for protein assembly and modification through Native Chemical Ligation (NCL). In this Emerging Area we highlight recent developments in a somewhat surprising route to thioesters: selective disruption of amides, the more stable carboxylic acid derivatives.

Nature of intermediates in organo-SOMO catalysis of alpha-arylation of aldehydes.

The intramolecular alpha-arylation of aldehydes via organo-SOMO catalysis was investigated using density functional theory (B3LYP and M06-2X functionals). The geometries, spin densities, Mulliken charges, and molecular orbitals of the reacting enamine radical cations were analyzed, and the nature of the resulting cyclized radical cation intermediates was characterized. In agreement with experimental observations, the calculated 1,3-disubstituted aromatic system shows ortho selectivity, while the 1,3,4-trisubstituted systems show para, meta (instead of ortho, meta) selectivity.

Semisynthetic Src SH2 domains demonstrate altered phosphopeptide specificity induced by incorporation of unnatural lysine derivatives.

Site-directed mutagenesis to the 20 natural amino acids becomes a limitation when evaluating subtle perturbations of an amino acid side chain within a protein. To further the study of Src homology 2 (SH2) domain ligand binding, we have developed a system allowing its semisynthesis from three fragments by native chemical ligation. We have replaced a key lysine residue with lysyl derivatives possessing progressively shorter aliphatic side chains.