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Diisopropylzinc alkylation of pyrimidine aldehydes-the Soai reaction, with its astonishing attribute of amplifying asymmetric autocatalysis-occupies a unique position in organic chemistry and stands as an eminent challenge for mechanistic elucidation. A new paradigm of "mixed catalyst-substrate" experiments with pyrimidine and pyridine systems allows a disconnection of catalysis from autocatalysis, providing insights into the role played by reactant and alkoxide structure. The alkynyl substituent favorably tunes catalyst solubility, aggregation, and conformation while modulating substrate reactivity and selectivity. The alkyl groups and the heteroaromatic core play further complementary roles in catalyst aggregation and substrate binding. In the study of these structure-activity relationships, novel pyridine substrates demonstrating amplifying autocatalysis were identified. Comparison of three autocatalytic systems representing a continuum of nitrogen Lewis basicity strength suggests how the strength of N-Zn binding events is a predominant contributor toward the rate of autocatalytic progression.

The Soai reaction has profoundly impacted chemists' perspective of autocatalysis, chiral symmetry breaking, absolute asymmetric synthesis and its role in the origin of biological homochirality. Here we describe the unprecedented observation of asymmetry-amplifying autocatalysis in the alkylation of 5-(trimethylsilylethynyl)pyridine-3-carbaldehyde using diisopropylzinc. Kinetic studies with a surrogate substrate and spectroscopic analysis of a series of zinc alkoxides that incorporate specific structural mutations reveal a 'pyridine-assisted cube escape'. The new tetrameric cluster functions as a catalyst that activates the substrate through a two-point binding mode and poises a coordinated diisopropylzinc moiety for alkyl group transfer. Transition-state models leading to both the homochiral and heterochiral products were validated by density functional theory calculations. Moreover, experimental and computational analysis of the heterochiral complex provides a definitive explanation for the nonlinear behaviour of this system. Our deconstruction of the Soai system reveals the structural logic for autocatalyst evolution, function and substrate compatibility-a central mechanistic aspect of this iconic transformation.

The Pictet-Spengler reaction is a valuable route to 1,2,3,4-tetrahydro-β-carboline (THBC) and isoquinoline scaffolds found in many important pharmaceuticals. Strictosidine synthase (STR) catalyzes the Pictet-Spengler condensation of tryptamine and the aldehyde secologanin to give (S)-strictosidine as a key intermediate in indole alkaloid biosynthesis. STRs also accept short-chain aliphatic aldehydes to give enantioenriched alkaloid products with up to 99% ee STRs are thus valuable asymmetric organocatalysts for applications in organic synthesis. The STR catalysis of reactions of small aldehydes gives an unexpected switch in stereopreference, leading to formation of the (R)-products. Here we report a rationale for the formation of the (R)-configured products by the STR enzyme from Ophiorrhiza pumila (OpSTR) using a combination of X-ray crystallography, mutational, and molecular dynamics (MD) studies. We discovered that short-chain aldehydes bind in an inverted fashion compared to secologanin leading to the inverted stereopreference for the observed (R)-product in those cases. The study demonstrates that the same catalyst can have two different productive binding modes for one substrate but give different absolute configuration of the products by binding the aldehyde substrate differently. These results will guide future engineering of STRs and related enzymes for biocatalytic applications.

The synchrotron technique of micro X-ray absorption near-edge structure spectroscopy at the sulfur K-edge (S-XANES) provides a unique opportunity to measure the proportion of different oxidation states of sulfur (S) in silicate glasses. Although applied extensively in the analysis of basaltic silicate glasses, few S-XANES studies have investigated variations in S oxidation states with fO2 in felsic silicate glasses. In addition, no study has systematically compared the S-XANES results obtained from the same samples at different photon flux densities to quantify the relationship between exposure time and changes in S speciation in silicate glass, as has been done for Fe and V. This study evaluates observed differences in S speciation measured in experimentally produced H2O-saturated dacitic glasses over a range of reducing to oxidizing conditions (from log fO2 = ΔFMQ-0.7 to ΔFMQ+3.3; FMQ is the fayalite-magnetite-quartz mineral redox buffer) and equilibrated at 1000 °C and 300 MPa. S-XANES spectra were collected at three different photon flux densities using three microspectroscopy beamlines. As is observed in S-XANES analyses of basaltic silicate glasses, beam-induced changes to the S6+/ΣS are observed as a function of photon flux density and beam exposure time. Our results demonstrate that silicate glasses of dacitic composition undergo beam-induced photo-reduction in samples equilibrated at ΔFMQ > +1.75 and photo-oxidation if equilibrated at ΔFMQ < +1. The time required to observe beam-induced changes in the spectra varies as a function of flux density, and our study establishes an upper photon density limit at ~1.0 × 1012 photons/μm2. The S6+/ΣS calculated from spectra collected below this absorbed photon limit at intermediate flux densities (~1–4 × 109 photons/s per μm2) are affected by beam damage, as no conditions were found to be completely free of beam-induced changes. However, the S6+/ΣS ratios calculated below the limit at intermediate flux densities are consistent with thermodynamic constraints, demonstrating that S6+/ΣS ratios calculated from S-XANES spectra can be considered reliable for estimating the oxygen fugacity. Our results carry important implications for the S budget of felsic magmas and dissolution mechanisms in evolved melts. While our results from all three flux densities show the presence of S4+ dissolved in relatively oxidized (ΔFMQ > +1.75) dacitic glass, even in the spectra exposed to the lowest photon densities, we are unable to rule out the possibility that the S4+ signal is the result of instantaneous X-ray irradiation induced beam damage using S-XANES alone. When our spectra are compared to S-XANES spectra from basaltic silicate glasses, important differences exist in the solubility of S2− and S6+ between dacitic silicate melts, pointing to differences in solubility mechanisms as melt composition changes. This study highlights the need for further investigation into beam damage systematics, presence of S4+, and the solubility mechanisms of different oxidation states of S as silicate melt composition changes. [ABSTRACT FROM AUTHOR]

Iron oxide-copper-gold (IOCG) and iron oxide-apatite (IOA) deposits are important sources of Cu and Fe, respectively. They contain abundant Fe-oxides and may contain Au, Ag, Co, rare earth elements (REEs), U, Ni, and V as economically important by-products. In Peru, the Mina Justa IOCG deposit is located next to the giant Marcona IOA deposit. Constraining the timing of Fe and Cu mineralization at Mina Justa is fundamental to understanding the duration and type of processes that generated this mineral deposit, and ultimately to testing the genetic link with other deposits in the area. Previous authors used alteration minerals to indirectly date Cu mineralization at Mina Justa at around 100 Ma. We report Ar/Ar dates of actinolite, U-Pb dates of magnetite, apatite, and titanite collected by in situ laser-ablation-multicollector-inductively coupled plasma-mass spectrometry, and Re-Os thermal ionization mass spectrometry dates for sulfides. These results indicate that Cu mineralization at Mina Justa occurred at ca. 160 Ma and that Fe mineralization is older and coeval with the neighboring Marcona IOA deposit, consistent with Cu mineralization overprinting IOA-style mineralization at Mina Justa. [ABSTRACT FROM AUTHOR]

We report a facile method to synthesize stereodefined quaternary centers from reactions of arynes and related strained intermediates using β-ketoester-derived substrates. The conversion of β-ketoesters to chiral enamines is followed by reaction with in situ generated strained arynes or cyclic alkynes. Hydrolytic workup provides the arylated or alkenylated products in enantiomeric excesses as high as 96%. We also describe the one-pot conversion of a β-ketoester substrate to the corresponding enantioenriched α-arylated product. Computations show how chirality is transferred from the N-bound chiral auxiliary to the final products. These are the first theoretical studies of aryne trapping by chiral nucleophiles to set new stereocenters. Our approach provides a solution to the challenging problem of stereoselective β-ketoester arylation/alkenylation, with formation of a quaternary center.

A Friedel-Crafts alkylation is described that efficiently transforms tryptophan-containing peptides into macrocycles of varying ring connectivity. Factors are surveyed that influence the distribution of regioisomers, with a focus on indole C3-alkylations leading to bridged endo-pyrroloindolines. We probe the stability and stereochemistry of these pyrroloindolines, study their rearrangement to C2-linked indolic macrocycles, and demonstrate a scalable, stereoselective synthesis of this compound class. Placing the macrocyclization in sequence with further template-initiated annulation leads to extraordinary polycyclic products and further demonstrates the potential for this chemistry to drive novel peptidomimetic lead discovery programs.

Dimeric indole alkaloids are structurally diverse natural products that have attracted significant attention from the synthetic and biosynthetic communities. Here, we describe the characterization of a P450 monooxygenase CnsC from Penicillium that catalyzes the heterodimeric coupling between two different indole moieties, tryptamine and aurantioclavine, to construct vicinal quaternary stereocenters and yield the heptacyclic communesin scaffold. We show, via biochemical characterization, substrate analogues, and computational methods that CnsC catalyzes the C3-C3' carbon-carbon bond formation and controls the regioselectivities of the pair of subsequent aminal bond formations to yield the communesin core. Use of ω-N-methyltryptamine and tryptophol in place of tryptamine led to the enzymatic synthesis of isocommunesin compounds, which have not been isolated to date.

Recent retrospective studies suggested that early postoperative infections might be associated with a survival benefit for extremity osteosarcoma patients, but the reported results have been conflicting. The files of 437 patients with a newly diagnosed, high-grade osteosarcoma of the extremities treated at 5 referral centers in Germany and Austria between 1989 and 2016 were retrospectively evaluated. All patients underwent multi-agent chemotherapy and limb-sparing tumor excision, followed by endoprothetic replacement. We used the Kaplan–Meier method to calculate survival curves, which we compared with the log-rank test. With a median follow-up of 100 months (interquartile range, 49–155 months), local recurrence (LR) probability, event-free survival (EFS), and disease-specific survival (DSS) after 5 years in this selected patient cohort amounted to 5%, 67%, and 79%, respectively, and 46 patients (10.5%) developed an early postoperative infection. We found no significant differences in LR, EFS, or DSS between patients with and without early infections, and there were no differences in known prognostic factors between the two groups. However, in subgroup analyses patients with a poor response to neoadjuvant chemotherapy and an early infection had a better DSS compared to patients without early infections (93% vs. 62% after 5 years, p = 0.044). Provided that our findings can be validated in separate patient cohorts, we believe that patient outcome after adjuvant immunomodulatory treatments in osteosarcoma patients should be evaluated and reported separately for good and poor responders to neoadjuvant chemotherapy in future studies.